Process for improved opioid synthesis

ABSTRACT

Compounds and compositions for use as starting materials or intermediate materials in the preparation of opioids including, e.g., oxymorphone base and/or an oxymorphone salt; processes for preparing these compounds and compositions; uses of these compounds and compositions in the preparation of APIs and pharmaceutical dosage forms; and uses of said APIs and pharmaceutical dosage forms in the treatment of medical conditions.

The present invention is in the field of pharmaceutical compositionscomprising opioids and in the field of pharmaceutical opioid synthesis.It provides compounds and compositions for use as starting materials orintermediate materials in the preparation of opioids including, e.g.,oxymorphone base and/or an oxymorphone salt; processes for preparingthese compounds and compositions; uses of these compounds andcompositions in the preparation of APIs and pharmaceutical dosage forms;and uses of said APIs and pharmaceutical dosage forms in the treatmentof medical conditions.

BACKGROUND OF THE INVENTION

Opioids like oxymorphone and its hydrochloride salt have long been usedas analgesics.

Oxymorphone base is conventionally prepared by O-demethylation ofoxycodone. Oxymorphone base can also be prepared by oxidation oforipavine to 14-hydroxymorphinone, and reducing the 14-hydroxymorphinoneto oxymorphone base. A route for the preparation of oxymorphone viaoxidation of oripavine to 14-hydroxymorphinone is illustrated in Scheme1:

Once the oxymorphone base has been prepared, it is usually reacted withan acid to produce an oxymorphone salt, typically oxymorphonehydrochloride, as shown below in Scheme 2:

The oxidation step in the synthetic route illustrated in Scheme 1 canyield by-products which may be converted into other by-products duringfurther conversion of the oxidation product (e.g., during the reactionshown in Scheme 2) or may be carried over into the final opioidcompound, final pharmaceutical composition or final dosage form. Theseby-products may be undesired in the final pharmaceutical composition orfinal dosage form. Separation of these by-products from the final opioidmay often be difficult, time-consuming and not volume efficient (e.g.,if a separation by HPLC is required).

For example, during oxidation of oripavine to 14-hydroxymorphinone,certain by-products can be formed, e.g., 8-hydroxyoxymorphone. Theseby-products can be converted to 14-hydroxymorphinone when HCl is added,as illustrated in Scheme 3:

Thus, the 14-hydroxymorphinone intermediate shown in Scheme 1 is notonly the immediate precursor to oxymorphone, it is also often found inthe final oxymorphone salt used in pharmaceutical compositions, e.g., inoxymorphone hydrochloride. 14-hydroxymorphinone belongs to a class ofcompounds known as α,β-unsaturated ketones (ABUKs). These compoundscontain a substructural component (the α,β-unsaturated ketone component)which produces a structure-activity relationship alert for genotoxicity.Their presence may be undesired in a pharmaceutical composition. Someregulatory authorities do not approve a pharmaceutical composition ordosage form for use and sale to the public if the amount of ABUKs in thepharmaceutical composition or dosage form exceeds the amount set bythese authorities.

The conventional oxymorphone hydrochloride compositions would thus haveto be subjected to one or more additional processing steps (e.g.,hydrogenation, multiple recrystallizations, etc.) to reduce the amountof 14-hydroxymorphinone or its hydrochloride salt in the oxymorphonehydrochloride compositions below the limit set by the FDA or anotherregulatory authority, before these compositions could be incorporatedinto pharmaceutical dosage forms and/or administered to humans. Theseadditional processing steps typically increase the production costs ofpharmaceutical dosage forms, and have the potential to form newcompounds and/or increase amounts of certain compounds above the limitsset by the regulatory authorities for these compounds.

The conventional processes for preparing oxymorphone or oxymorphonesalts from oxycodone or from oripavine are also often not very volumeand cost efficient in their oxidation step, or they are complicated(e.g., the O-demethylation of oxycodone) and require specific equipment.

There is a continuing need for oxymorphone compositions and oxymorphonesalt compositions which may directly be incorporated into pharmaceuticaldosage forms without or with a reduced number of additional processingsteps, processes for preparing these compositions, and starting andintermediary compounds or compositions used in and/or produced by theseprocesses.

There is also a continuing need for processes which allow for anincrease in volume efficiency, comprise a reduced number of processingsteps and/or reduce manufacturing costs of processes for preparation ofpharmaceutical compositions and dosage forms containing opioids, ascompared to the conventional processes.

There is also a continuing need for processes for preparing opioidswhich exhibit a reduced amount of by-products in the processintermediates (e.g., of 8-hydroxyoxymorphone in the intermediate14-hydroxymorphinone) and/or in the final opioid product (e.g., of14-hydroxymorphinone in oxymorphone hydrochloride).

SUMMARY OF THE INVENTION

The invention is directed to compounds and compositions for use asstarting materials or intermediate materials in the preparation ofopioids including, e.g., oxymorphone base and/or an oxymorphone salt;processes for preparing these compounds and compositions; uses of thesecompounds and compositions in the preparation of APIs and pharmaceuticaldosage forms; and uses of said APIs and pharmaceutical dosage forms inthe treatment of medical conditions.

The compounds and compositions of the invention allow, inter alia, formore efficient (e.g., more volume efficient) and cheaper preparation ofpharmaceutical products comprising opioids (e.g., oxymorphone salts)than conventional processes, e.g., because the compounds andcompositions of the invention may be incorporated into pharmaceuticaldosage forms without additional processing steps (e.g., without being(re)hydrogenated and/or (re)crystallized prior to the incorporation intothe pharmaceutical dosage forms).

In one aspect, the invention is directed to compounds and compositionsfor use as starting materials or intermediate materials in thepreparation of oxymorphone base and/or oxymorphone salts; processes forpreparing these compounds and compositions; and uses of these compoundsand compositions in the preparation of pharmaceutical dosage formscontaining oxymorphone or an oxymorphone salt. These compounds,compositions, and dosage forms in preferred embodiments comprise or areprepared from a salt of 14-hydroxymorphinone or compositions comprisinga salt of 14-hydroxymorphinone. They may be used in the treatment ofmedical conditions (e.g., pain, addiction, cough, diarrhea, etc.).

In another aspect, the invention is directed to compositions comprisinga salt of 14-hydroxymorphinone (e.g., 14-hydroxymorphinone sulfate),which compositions are useful as starting materials or intermediatematerials in the preparation of pharmaceutical compositions and dosageforms comprising oxymorphone base and pharmaceutical compositions anddosage forms comprising an oxymorphone salt (e.g., oxymorphonehydrochloride).

In one aspect, the present invention is directed to a process forpreparing a compound of formula V, or a solvate thereof, by oxidation ofa compound of formula I (Scheme 4):

Said compound of formula V contains a compound of formula II asstructural element:

wherein R¹ and R² are defined as below. An example of a compound offormula II is 14-hydroxymorphinone. In the compound of formula V, thecompound of formula II is typically protonated by a proton (H⁺), andthus forms a cation. For example, when n=2, the two protons and twocompounds of formula II which are present in the compound of formula Vform two cations of formula II in its protonated form.

Said compound of formula V or solvate thereof may be precipitated fromthe reaction mixture formed in the reaction of Scheme 4. The compound offormula V or solvate thereof can then be used as a starting material(either isolated or directly) for preparing other opioids, for example,a compound of formula IV:

wherein R¹ and R² are defined as below,or an (optionally pharmaceutically acceptable) salt or solvate thereof.The compound of formula V may or may not be isolated from the reactionmixture prior to preparing the compound of formula IV. In one aspect,the compound of formula V or solvate thereof is used as a startingmaterial for preparing a salt of the compound of formula IV or solvatethereof, wherein the anion in the salt of the compound of formula IV isthe same X^(n−) as in the compound of formula V.

The present invention is also directed to the compounds of formula V andto other opioids prepared by the processes of the present invention, tocompositions comprising said compounds, and to their use in thepreparation of pharmaceutical compositions and dosage forms.

Hence, in certain embodiments, the present invention provides a processfor preparing a compound of formula V or a solvate thereof

from a compound of formula I or a salt or solvate thereof, the processcomprising:

(a) oxidizing the compound of formula I; and(b) adding an acid H⁺ _(n)X^(n+) to the reaction mixture before, duringand/or after the oxidation reaction, whereinR¹ is —H, —(C₂-C₇)alkyl, aralkyl, —(C₂-C₆)alkenyl, —SiR³ ₃,—(C₃-C₇)cycloalkyl, —(C₁-C₇)alkyl-(C₃-C₇)cycloalkyl,—(C₃-C₇)cycloalkenyl, —(C₁-C₇)alkyl-(C₃-C₇)cycloalkenyl, —CR⁴₂—O—(C₁-C₆)alkyl, —C(halo)₃, —CH₂(halo), —CH(halo)₂, —SO₂R⁵, or anO-protecting group;R² is —H, —CH₃, —(C₂-C₇)alkyl, —(C₂-C₄)alkenyl, benzyl,—(C₁-C₇)alkyl-(C₃-C₇)cycloalkyl, —CN, or an N-protecting group;each R³ is independently selected from aryl, —(C₁-C₆)alkyl and—(C₁-C₆)alkoxy;each R⁴ is independently selected from —H and —(C₁-C₆)alkyl;R⁵ is —(C₆-C₁₄)aryl or —(C₁-C₆)alkyl;X^(n−) is an anion selected from the group consisting of Cl⁻, HSO₄ ⁻,SO₄ ²⁻, methanesulfonate, tosylate, trifluoroacetate, H₂PO₄ ⁻, HPO₄ ²⁻,PO₄ ³⁻, oxalate, perchlorate, and any mixtures thereof; andn is 1, 2, or 3.

In a preferred embodiment, the acid H⁺ _(n)X^(n−) is added to thereaction mixture before or during the oxidation reaction. Morepreferably, the acid H⁺ _(n)X^(n−) is present in the reaction mixtureduring the complete oxidation reaction, i.e. it is added before thestart of the oxidation reaction, or at the start of the oxidationreaction.

In addition to the compound of formula V, the oxidation of compound offormula I may generate a compound of formula III or a salt or solvatethereof. The compound of formula III may be formed as follows:

The compound of formula III is an 8-hydroxy compound, e.g.,8-hydroxyoxymorphone. The stereoconfiguration at C-8 of formula III canbe either alpha (8α) or beta (8β). The 8α and 8β stereoconfiguration areexemplified for 8-hydroxyoxymorphone in Scheme 6. The compound offormula III may be the 8α compound, or the 8β compound, or a mixture ofthe 8α compound of formula III and the 8β compound of formula III.

The formation of the compound of formula V or solvate thereof can reducethe amount of the compound of formula III which is present afteroxidation of the compound of formula I, as compared to a process wherethe compound of formula I is oxidized without involving the compound offormula V.

Once the compound of formula V is formed, the compound of formula V orsolvate thereof can be precipitated and optionally isolated. Typically,at least some compound of formula III or salt or solvate thereof remainsin the supernatant. Thus, a separation of the compound of formula IIIfrom the compound of formula V or solvate thereof may be achieved by theprecipitation. The precipitated and optionally isolated precipitate,which contains the compound of formula V or the solvate thereof, maycontain a lower ratio of the compound of formula III to the compound offormula V than the ratio of the compound of formula III to the compoundof formula V in the mother liquor.

Thus, for example, the formation of a 14-hydroxymorphinone salt(compound of formula V) and the isolation of the precipitated saltappear to prevent or reduce (i) the formation of 8-hydroxyoxymorphoneduring oxidation of oripavine, as compared to processes which do notinvolve the formation of the compound of formula V, (ii) the presence of8-hydroxyoxymorphone in a composition comprising oxymorphone base madevia a compound of formula V, and (iii) the presence of8-hydroxyoxymorphone or a salt thereof and 14-hydroxymorphinone or asalt thereof in an oxymorphone salt or in a pharmaceutical compositioncomprising an oxymorphone salt. The same applies to other compounds offormula V and the corresponding compounds of formulae I, II, III, andIV.

Pharmaceutical compositions prepared by processes of the presentinvention may be quantitatively different from pharmaceuticalcompositions prepared by conventional processes which do not utilize thecompound of formula V, and may offer advantages over the compositionsprepared by conventional processes, e.g., in terms of safety, efficiencyand reduced manufacturing costs. For example, these compositions maycontain less by-products and/or require less or no further processingsteps after synthesis of their API.

Moreover, adding the acid H⁺ _(n)X^(n−) may allow for a more volumeefficient oxidation process, as compared to the conventional oxidationreaction which is exemplified in the Background Section for oxidation oforipavine. The volume efficiency of a subsequent reaction utilizing thecompound of formula V or solvate thereof as starting material may alsobe improved, e.g., when the compound of formula V or solvate thereof isused in its precipitated form.

An exemplary embodiment of the process for preparing a compound offormula V is a process for preparing 14-hydroxymorphinone as its sulfatesalt (or a solvate thereof), which encompasses the oxidation oforipavine illustrated in Scheme 7:

In one preferred embodiment, the compound of formula I is oripavine, thecompound of formula II is 14-hydroxymorphinone, the acid H⁺ _(n)X^(n−)is H₂SO₄, and the compound of formula V is a sulfate of14-hydroxymorphinone:

or a solvate thereof.

The present invention, in certain embodiments, provides a compoundhaving the formula V or a solvate thereof

wherein R¹, R², X^(n−) and n are defined as above.

In one embodiment of the present invention, the compound of formula V is

or a solvate thereof,wherein R¹ and R² are defined as above.

In one embodiment, the compound of formula V is

or a solvate thereof. In the context of the present invention, thiscompound will be designated as 14-hydroxymorphinone sulfate. Because ofits stoichiometric composition, it may also be designated asbis(14-hydroxymorphinone)sulfate. The terms (compound of formulaII)sulfate (e.g., 14-hydroxymorphinone sulfate) and bis(compound offormula II)sulfate (e.g., bis(14-hydroxymorphinone)sulfate) are usedinterchangeably in the context of the present invention.

Moreover, provided is a process for preparing a compound of formula IVor an (optionally pharmaceutically acceptable) salt or solvate thereof,the process comprising a conversion of a compound of formula V or asolvate thereof to a compound of formula IV or salt or solvate thereof,e.g., by hydrogenation of the compound of formula V or solvate thereof.In said process, the compound of formula V or a solvate thereof may beused as a starting material or as an intermediate material. In each ofthese cases, said compound of formula V or solvate thereof may beprepared by the process starting from the compound of formula I asdescribed above.

Said process for preparing a compound of formula IV or an (optionallypharmaceutically acceptable) salt or solvate thereof may be representedby the following reaction Scheme 8:

wherein R¹, R², X^(n−) and n are defined as above.

The process may comprise the steps of providing a solution or suspensionof the compound of formula V or a solvate thereof; and reducing thecompound of formula V or solvate thereof to the compound of formula IVor an (optionally pharmaceutically acceptable) salt or solvate thereof.

Hence, the present invention also provides a process for preparing acompound of formula IV or a salt or solvate thereof from a compoundhaving formula V or a solvate thereof

the process comprising the steps of(e) providing a solution or suspension of the compound having formula Vor a solvate thereof; and(f) reducing the compound of formula V to the compound of formula IV,wherein R¹, R², X^(n−) and n are defined as above.

After the reduction reaction, the compound of formula IV may be presentas its salt or solvate in the reaction mixture, e.g., as its sulfatesalt. In a subsequent step, it may be converted into its free baseand/or converted into a different salt or solvate, e.g., apharmaceutically acceptable salt or solvate. It may be isolated from thereaction mixture in one or more of these forms.

In one embodiment, the compound of formula IV is present, e.g., as itssulfate salt in the reaction mixture, and this sulfate salt or a solvatethereof may be optionally isolated from the reaction mixture, e.g. byprecipitation and subsequent isolation of the precipitate. In saidembodiment, the process may be represented by the following reactionscheme:

the process comprising the steps of(e) providing a solution or suspension of the compound having formula Vor a solvate thereof; and(f) reducing the compound of formula V to the salt of the compound offormula IV with H⁺ _(n)X^(n−); and optionally(g) isolating the salt of the compound of formula IV with H⁺ _(n)X^(n−),wherein R¹, R², X^(n−) and n are defined as above, and X^(n−) ispreferably SO₄ ²⁻. This reduction is performed directly from salt tosalt, i.e. without intermediate isolation of the free base II. Moreover,the salt of the compound of formula IV prepared by said process ispreferably oxymorphone sulfate or a solvate thereof. I.e., in apreferred aspect of this process, 14-hydroxymorphinone sulfate (or asolvate thereof) is reduced to oxymorphone sulfate (or a solvatethereof). A reduction of V to the salt of IV wherein X istrifluoroacetate is also specifically considered in the context of thepresent invention.

The present invention also provides a process wherein a compound offormula II is converted to a salt of the compound of formula IV with H⁺_(n)X^(n−), e.g. to a sulfate salt of formula IV. This conversion isachieved by reducing the compound of formula II in the presence of theacid H⁺ _(n)X^(n−). The acid H⁺ _(n)X^(n−) may be added before or duringthe reduction reaction. The resulting salt of the compound of formula IVwith H⁺ _(n)X^(n−) may be optionally isolated from the reaction mixture,e.g. by precipitation and subsequent isolation of the precipitate. Insaid embodiment, the process may be represented by the followingreaction scheme:

the process comprising the steps of(e) providing a solution or suspension of the compound having formula IIor a solvate thereof; and(f) reducing the compound of formula II in the presence of an acid H⁺_(n)X^(n−) to the salt of the compound of formula IV with H⁺ _(n)X^(n−);and optionally(g) isolating the salt of the compound of formula IV with H⁺ _(n)X^(n−),wherein R¹, R², X^(n−) and n are defined as above, and X^(n−) ispreferably SO₄ ²⁻. This reduction is performed using the free base II.Said base may be provided by isolating it as intermediate from acompound of formula V. Moreover, the salt of the compound of formula IVprepared by said process is preferably oxymorphone sulfate or a solvatethereof. I.e., in a preferred aspect of this process,14-hydroxymorphinone base is converted to oxymorphone sulfate (or asolvate thereof). A process for preparing a salt of IV wherein X^(n−) istrifluoroacetate is also specifically considered in the context of thepresent invention.

It should be apparent to a person skilled in the art that the terms“salt” and “solvate” in the present specification encompass “apharmaceutically acceptable salt” and “a pharmaceutically acceptablesolvate”, respectively. The formation of a pharmaceutically acceptablesalt or solvate may be achieved either directly or by the preparation ofa pharmaceutically unacceptable salt or solvate and a subsequentconversion to the pharmaceutically acceptable salt or solvate. Aconversion of one pharmaceutically acceptable salt or solvate to anotherpharmaceutically acceptable salt or solvate is also possible.

The processes of the present invention are suitable for reducing theamount of a compound of formula II and/or a compound of formula III in acompound of formula IV or a salt or solvate thereof prepared directlyfrom the compound of formula V or via a process utilizing the compoundof formula V as an intermediate, in comparison to processes using otherintermediates or starting materials. In particular, using the compoundof formula V allows for the reduction of the amount of compound offormula III in the compound of formula IV. This, in turn, may result inlower amounts of compound of formula II which may be formed duringconversion of the compound of formula IV to a salt thereof by acidaddition after step (f) of the process described above.

The product obtainable by said process encompassing steps (e) and (f),i.e., a compound of formula IV

wherein R¹ and R² are defined as above,or an (optionally pharmaceutically acceptable) salt or solvate thereof,is also provided by the present invention. In one embodiment, saidcompound of formula IV is provided as its salt or a solvate thereofhaving X^(n−) as anion, in particular as its sulfate salt or a solvatethereof. As already indicated above, the product of said processencompassing steps (e) and (f) is preferably oxymorphone sulfate. In oneaspect of the present invention, oxymorphone sulfate as a compounditself or a solvate thereof is also encompassed by the presentinvention. In another aspect of the present invention, oxymorphonetrifluoroacetate or a solvate thereof is also encompassed as a compounditself.

Said compound of formula IV or (optionally pharmaceutically acceptable)salt or solvate thereof, when prepared by a process according to presentinvention, may comprise only very low amounts of a compound of formulaII. As explained above, under the conditions described in the prior art,a compound of formula II may be formed from the compound of formula IIIwhen preparing the compound of formula IV or a salt or solvate thereof.In particular, the compound of formula IV or the pharmaceuticallyacceptable salt or solvate thereof according to the present inventionmay comprise an amount of the compound of formula II which is below adesired threshold amount, e.g., a threshold amount mandated by theregulatory authorities for the approval of pharmaceutical compositionsfor use and sale to the public, and/or it comprises an amount of thecompound of formula III

wherein R¹ and R² are defined as above,or a salt or solvate thereof,which is insufficient to increase the amount of a compound of formula IIor a salt or solvate thereof, upon further processing of the compound offormula IV or a salt or solvate thereof, above said threshold amount.

In certain embodiments, the present invention provides a salt of acompound of formula IV, or a solvate thereof. In certain embodiments,the present invention provides a hydrochloride of a compound of formulaIV, e.g., oxymorphone hydrochloride, or a solvate thereof. In certainembodiments, the present invention provides a sulfate of a compound offormula IV, e.g., oxymorphone sulfate, or a solvate thereof. In certainembodiments, the present invention provides a trifluoroacetate of acompound of formula IV, e.g., oxymorphone trifluoroacetate, or a solvatethereof.

In yet another aspect, the invention is directed to a pharmaceuticalcomposition comprising a salt of a compound of formula IV (e.g., anoxymorphone salt), a compound of formula III (e.g.,8-hydroxyoxymorphone) or a salt thereof, and a compound of formula II(e.g., 14-hydroxymorphinone) or a salt thereof, the composition having aratio of (i) the compound of formula III (e.g., 8-hydroxyoxymorphone) to(ii) the compound of formula II (e.g., 14-hydroxymorphinone) which isthe same or about the same as the ratio of (i) the compound of formulaIII (e.g., 8-hydroxyoxymorphone) to (ii) the compound of formula II(e.g., 14-hydroxymorphinone) in the composition from which it wasdirectly prepared from (i.e., within 20% of the ratio of the compositionit was prepared from). The compositions of the invention therefore allowfor more efficient and cheaper preparation of pharmaceuticalcompositions. For example, the preparation of oxymorphone hydrochloridemay be more efficient because the ratio of (i) the 8-hydroxyoxymorphoneto (ii) the 14-hydroxymorphinone in the final product is known beforethe final product is manufactured and the manufacturing process may beadjusted or planned based on this ratio.

The present invention further provides pharmaceutical compositions anddosage forms, which comprise a compound of formula IV or apharmaceutically acceptable salt or solvate thereof as defined above(e.g., oxymorphone hydrochloride). In certain embodiments, thesepharmaceutical compositions have a different by-product profile and mayhave a different efficacy than pharmaceutical compositions prepared viathe free base of a compound of formula II, rather than via the compoundof formula V or a solvate thereof. In certain embodiments, the contentof the compound II in these pharmaceutical compositions differs from thecontent of the compound of formula II in pharmaceutical compositionsprepared via the free base of a compound of formula II, rather than viathe compound of formula V or a solvate thereof. This encompassespharmaceutical compositions comprising a compound of formula IV or thepharmaceutically acceptable salt or solvate thereof and a compound offormula II or a salt or solvate thereof in an amount which is below adesired threshold amount, e.g., a threshold amount mandated by theregulatory authorities for the approval of these compositions for useand sale to the public. It also encompasses pharmaceutical compositionscomprising, in addition to the compound of formula IV or thepharmaceutically acceptable salt or solvate thereof, a compound offormula III or a salt or solvate thereof in an amount which isinsufficient to increase the levels of the compound of formula II or asalt or solvate thereof, upon further processing of the pharmaceuticalcompositions as described in the prior art, above said desired thresholdamount of the compound of formula II. It also encompasses pharmaceuticalcompositions comprising, in addition to the compound of formula IV orthe pharmaceutically acceptable salt or solvate thereof, a compound offormula II or a salt or solvate thereof, and a compound of formula IIIor a salt or solvate thereof, wherein the compound of formula III ispresent in an amount which is insufficient to increase the levels of thecompound of formula II, upon further processing as described in theprior art, above said desired threshold amount.

The present invention also provides pharmaceutical compositions anddosage forms comprising a compound of formula IV or a pharmaceuticallyacceptable salt or solvate thereof, which is selected from the groupcomprising or consisting of oxymorphone, naltrexone, naloxone,nalfurafine, methylnaltrexone, and pharmaceutically acceptable salts andsolvates of any of the foregoing, wherein the amount of the compound offormula III in the pharmaceutical compositions or dosage forms isinsufficient to increase the total amount of compound of formula II inthe pharmaceutical compositions and dosage forms, upon furtherprocessing of the pharmaceutical compositions or dosage forms asdescribed in the prior art, above said desired threshold amount. In apreferred embodiment, the compound of formula IV or pharmaceuticallyacceptable salt or solvate thereof is oxymorphone or a pharmaceuticallyacceptable salt or solvate thereof.

The present invention is further directed to pharmaceutical compositionsand dosage forms formed as the result of carrying out the processes ofthe invention, as well as methods for using these pharmaceuticalcompositions and dosage forms in the treatment of medical conditions.The immediate products formed by carrying out the processes of theinvention may be suitable as pharmaceutical compositions themselves,without further processing steps.

Compounds and compositions in accordance with the present invention,including intermediate compositions, may be used, e.g., in themanufacture of pharmaceutical compositions and dosage forms comprisingat least one compound of formula IV or a pharmaceutically acceptablesalt or solvate thereof, including the compounds of formula IV which arespecifically indicated in the present description. These pharmaceuticalcompositions and dosage forms can be used to treat or prevent one ormore of the following medical conditions: pain, addiction, cough,constipation, diarrhea, insomnia associated with and/or caused by pain,cough or addiction, depression associated with and/or resulting frompain, cough or addiction, or a combination of two or more of theforegoing conditions, etc. A method for treatment or prevention of oneor more of these conditions by administration of a compound of formulaIV or a salt or solvate thereof to a patient is also provided by thepresent invention.

The use of a pharmaceutical composition or dosage form according to thepresent invention, comprising at least one compound of formula IV or apharmaceutically acceptable salt or solvate thereof, including thecompounds of formula IV which are specifically indicated in the presentdescription, in the manufacture of a medicament for the treatment of oneor more of these medical conditions is also part of the presentinvention.

DEFINITIONS

Unless otherwise specified, the following abbreviations and definitionsare used in the context of the present invention.

The undefined article “a” or “an” is intended to mean one or more of thespecies designated by the term following said article. For example, “acompound of formula II” encompasses one or more molecules of thecompound of formula II.

The term “about” in the context of the present application means a valuewithin 15% (±15%) of the value recited immediately after the term“about,” including any numeric value within this range, the value equalto the upper limit (i.e., +15%) and the value equal to the lower limit(i.e., −15%) of this range. For example, the phrase “about 100”encompasses any numeric value that is between 85 and 115, including 85and 115 (with the exception of “about 100%”, which always has an upperlimit of 100%). In a preferred aspect, “about” means±10%, even morepreferably ±5%, even more preferably ±1% or less than ±1%.

An “opioid” in its broadest sense encompasses all compounds usuallydesignated with said term in the art, including opioids which act as anagonist on opioid receptors and opioids which act as an antagonist onopioid receptors. Partial agonists and partial antagonists are alsoknown and are encompassed by the term “opioid”. Opioid agonists include,e.g., oxymorphone, oxycodone, noroxymorphone, nalfurafine and salts andsolvates of any of the foregoing. Opioid antagonists include, e.g.,naltrexone, methylnaltrexone, naloxone, nalmefene, and salts andsolvates of any of the foregoing. In the context of the presentapplication, the term “opioid” shall encompass a compound having one ofthe following scaffolds (which will be designated as “morphine scaffold”in the context of present invention):

The degree of unsaturation in the ring formed by atoms 5, 6, 7, 8, 14and 13 may vary (the ring may, e.g., just contain single bonds as incompounds of formula III, contain just one double bond as in compoundsof formula II, or contain two double bonds as in compounds of formulaI).

Thus, in the context of the present invention, the term “opioid” in itsbroadest sense encompasses compounds of formulae I, II, III, IV and V.In the processes of the present invention, opioids can serve as startingmaterials, intermediates, or final products. They can (for example incase of a compound having formula V) also serve as an intermediate orfinal product in one process and as a starting material in anotherprocess of the present invention. Whenever a “process for preparing anopioid” is mentioned herein, it will be clear from the context whichopioid is prepared. In a narrower sense, the term “opioid” shalldesignate compounds of formula IV and (optionally pharmaceuticallyacceptable) salts and solvates thereof. One of the objects of thepresent invention is the provision of processes for ultimately preparingcompounds of formula IV or pharmaceutically acceptable salts or solvatesthereof which can serve as APIs (e.g., oxymorphone or a pharmaceuticallyacceptable salt thereof), and their immediate precursors (e.g., acompound of formula V containing 14-hydroxymorphinone). Hence, in thecontext of present invention the term “opioid” will also be used forreferring to compounds of formula IV, whilst the term “opioid precursor”will also be used for referring to compounds of formula V.

The “threshold amount” of compound of formula II in pharmaceuticalcompositions and dosage forms may be set by regulatory authorities suchas the U.S. Food and Drug Administration (FDA) and can then be learnedfrom the latest version of the FDA guidelines (“Guidelines”) or, ifcertain compounds of formula II are not addressed in said Guidelines,from the latest version of the ICH Guidelines. In the context of thepresent invention, the threshold amount may be 10 ppm or less.

The term “8-hydroxy compound” in the context of the present applicationmeans a compound containing a hydroxyl group in position 8 of themorphine scaffold. In a narrower sense, it means a compound having thestructure of formula III:

whereinR¹ is —H, —(C₂-C₇)alkyl, aralkyl, —(C₂-C₆)alkenyl, —SiR³ ₃,—(C₃-C₇)cycloalkyl, —(C₁-C₇)alkyl-(C₃-C₇)cycloalkyl,—(C₃-C₇)cycloalkenyl, —(C₁-C₇)alkyl-(C₃-C₇)cycloalkenyl, —CR⁴₂—O—(C₁-C₆)alkyl, —C(halo)₃, —CH₂(halo), —CH(halo)₂, —SO₂R⁵, or anO-protecting group;R² is —H, —CH₃, —(C₂-C₇)alkyl, —(C₂-C₄)alkenyl, benzyl,—(C₁-C₇)alkyl-(C₃-C₇)cycloalkyl, —CN, or an N-protecting group;each R³ is independently selected from aryl, —(C₁-C₆)alkyl and—(C₁-C₆)alkoxy, preferably from —(C₁-C₄)alkyl and —(C₁-C₄)alkoxy, morepreferably —SiR³ ₃ is trimethylsilyl (TMS), tert-butyldimethylsilyl(TBDMS), triethylsilyl (TES), or triisopropylsilyl (TIPS);each R⁴ is independently selected from —H and —(C₁-C₆)alkyl, andpreferably is —H; R⁵ is —(C₆-C₁₄)aryl or —(C₁-C₆)alkyl;or a salt or solvate thereof. The term “8-hydroxy compound” includes the8α-hydroxy compound of formula III and/or the 8β-hydroxy compound offormula III.

As used in connection with the compounds of formula I, H, III, IV and Vof the present invention, the terms used herein have the followingmeaning:

“—(C₁-C₇)alkyl” means a straight chain or branched non-cyclichydrocarbon having 1, 2, 3, 4, 5, 6, or 7 carbon atoms. Representativestraight chain —(C₁-C₇)alkyls include -methyl, -ethyl, -n-propyl,-n-butyl, -n-pentyl, -n-hexyl, and -n-heptyl. A branched alkyl meansthat one or more straight chain —(C₁-C₅)alkyl groups, such as methyl,ethyl or propyl, replace one or both hydrogens in one or more —CH₂—groups of a straight chain alkyl. The total number of C atoms in abranched chain alkyl is from 3 to 7 C atoms. Representative branched—(C₁-C₇)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl,-iso-pentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,1,2-dimethylpentyl, and 1,3-dimethylpentyl.

“—(C₂-C₇)alkyl” means a straight chain or branched non-cyclichydrocarbon having 2, 3, 4, 5, 6, or 7 carbon atoms. Representativestraight chain —(C₂-C₇)alkyls include -ethyl, -n-propyl, -n-butyl,-n-pentyl, -n-hexyl, and -n-heptyl. A branched alkyl means that one ormore straight chain —(C₁-C₅)alkyl groups, such as methyl, ethyl orpropyl, replace one or both hydrogens in one or more —CH₂— groups of astraight chain alkyl. The total number of C atoms in a branched chainalkyl is from 3 to 7 C atoms. Representative branched —(C₂-C₇)alkylsinclude -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl,-neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,1,2-dimethylpentyl, and 1,3-dimethylpentyl.

“—(C₁-C₆)alkyl” means a straight chain or branched non-cyclichydrocarbon having 1, 2, 3, 4, 5, or 6 carbon atoms. Representativestraight chain —(C₁-C₆)alkyls include -methyl, -ethyl, -n-propyl,-n-butyl, -n-pentyl, and -n-hexyl. Representative branched—(C₁-C₆)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl,-iso-pentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethtylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

“—(C₁-C₅)alkyl” means a straight chain or branched non-cyclichydrocarbon having 1, 2, 3, 4, or 5 carbon atoms. Representativestraight chain —(C₁-C₅)alkyls include -methyl, -ethyl, -n-propyl,-n-butyl, and -n-pentyl. Representative branched —(C₁-C₅)alkyls include-iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl,-neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, and 1,2-dimethylpropyl.

“—(C₂-C₆)alkenyl” means a straight chain or branched non-cyclichydrocarbon having 2, 3, 4, 5, or 6 carbon atoms and including at leastone carbon-carbon double bond. Representative straight chain—(C₂-C₆)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-3-butenyl, -1,3-butadienyl, -1-pentenyl, -2-pentenyl, -3-pentenyl,-4-pentenyl, -1,3-pentadienyl, -1,4-pentadienyl, -2,4-pentadienyl,-1-hexenyl, -2-hexenyl, -3-hexenyl, -4-hexenyl, -5-hexenyl,-1,3-hexadienyl, -1,4-hexadienyl, -1,5-hexadienyl, -2,4-hexadienyl,-2,5-hexadienyl, -3,5-hexadienyl, -1,3,5-hexatrienyl. Representativebranched —(C₂-C₆)alkenyls include -iso-butylenyl, -iso-pentylenyl, andthe like.

“—(C₂-C₄)alkenyl” means a straight chain or branched non-cyclichydrocarbon having 2, 3, or 4 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched—(C₂-C₄)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-3-butenyl, -iso-butylenyl, -1,3-butadienyl, and the like.

“—(C₁-C₆)alkoxy” means a straight chain or branched non-cyclichydrocarbon having one or more ether groups and 1, 2, 3, 4, 5, or 6carbon atoms. Representative straight chain and branched —(C₁-C₆)alkoxysinclude -methoxy, -ethoxy, -methoxymethyl, -2-methoxyethyl,-5-methoxypentyl, -3-ethoxybutyl, (methoxymethoxy)methyl-,1-(methoxy)-1-methoxyethyl-, trimethoxymethyl-,2-((methoxy)methoxy)-2-methylpropyl-, 3-(1,1,1-trimethoxypropane),(methoxy)trimethoxymethyl-, (2,2,2-trimethoxyethoxy)-, and the like.

“—(C₃-C₇)cycloalkyl” means a saturated monocyclic hydrocarbon having 3,4, 5, 6, or 7 carbon atoms. Representative —(C₃-C₇)cycloalkyls are-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, and -cycloheptyl.

“—(C₃-C₇)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having atleast one carbon-carbon double bond in the cyclic system and 3, 4, 5, 6,or 7 carbon atoms. Representative —(C₃-C₇)cycloalkenyls include-cyclopropenyl, -cyclobutenyl, -cyclopentenyl, -cyclopentadienyl,-cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl,-cycloheptatrienyl, and the like.

“—C(halo)₃” means a methyl group where each of the hydrogens of themethyl group has been replaced with a halogen. Representative —C(halo)₃groups include —CF₃, —CCl₃, —CBr₃, and —Cl₃, and groups with mixedhalogens like —CF₂Cl.

“-Halogen” or “-halo” means —F, —Cl, —Br, or —I.

“Aralkyl” means any of the above-mentioned alkyl groups substituted withone, two, or three optionally substituted aryl groups. In oneembodiment, the aralkyl group is a —(C₁-C₆)alkyl substituted with oneoptionally substituted aryl group. Non-limiting exemplary aralkyl groupsinclude benzyl and phenethyl.

The term “aryl” itself refers to a monocyclic or bicyclic aromatic ringsystem having from six to fourteen carbon atoms (i.e., (C₆-C₁₄)aryl).Non-limiting exemplary aryl groups include phenyl (abbreviated as “Ph”),naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl,biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group ischosen from phenyl and naphthyl.

“O-protecting groups” or “oxygen protecting groups” include any groupwhich may be suitable to protect the oxygen from taking part in areaction, and which may be removed after the reaction. Examples of suchprotecting groups include acetate (Ac), benzoate, trifluoro benzoate,4-chlorobenzoate, pivaloate, methoxymethyl, benzyloxymethyl, benzyl,p-methoxybenzyl (PMB), tert-butyl dimethylsilyl (TBS), trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),tert-butyldiphenylsilyl (TBDPS), monochloroacetate, trifluoroacetate,levulinyl, 4-O-acetyl-2,2-dimethylbutanoate (ADMB), trityl,dimethoxytrityl, tosyl, mesyl, 9-fluoreneylmethoxycarbonyl (Fmoc),allyloxycarbonyl (Alloc) and naphthyl and 4-halobenzyl, among others.Further examples can be found in Wuts and Greene, Greene's ProtectiveGroups in Organic Synthesis, Wiley-Interscience, 4^(th) Edition (2006).

“N-protecting groups” or “nitrogen protecting groups” include any groupwhich may be suitable to protect the nitrogen from taking part in thereaction, and which may be removed after the reaction. Examples of suchprotecting groups include tert-butyloxycarbonyl (Boc), carbobenzyloxy(Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), Alloc, tosyl,benzenesulfonyl, trifluoromethylcarbonyl, and2,2,2-trichloroethoxycarbonyl (TroC). Further examples can be found inWuts and Greene, Greene's Protective Groups in Organic Synthesis,Wiley-Interscience, 4^(th) Edition (2006).

The term “solvate” in the context of the present application in itsbroadest sense means an association product of a compound or salt of thepresent invention with a solvent molecule. The molar ratio of solventmolecule(s) per compound molecule may vary. The molar ratio of solventto compound/salt in the solvate may be 1 (e.g., in a monohydrate), morethan 1 (e.g., 2, 3, 4, 5 or 6 in a polyhydrate), or less than 1 (e.g.,0.5 in a hemihydrate). The molar ratio need not be an integer ratio, itcan also be, e.g., 0.5 (as in a hemihydrate) or 2.5. For example, 1molecule water per molecule of 14-hydroxymorphinone sulfate is bound in14-hydroxymorphinone sulfate monohydrate. Applied to the compounds offormula I, II, III, IV and V of the present invention or, whereappropriate, to salts thereof, the solvate is in certain embodiments ahydrate, for example a monohydrate, dihydrate, trihydrate, tetrahydrate,pentahydrate or hexahydrate, or a hydrate wherein the ratio of water permolecule is not necessarily an integer, but within the range of from 0.5to 10.0. In certain embodiments, the solvate is a hydrate wherein theratio of water per molecule is within the range of from 1 to 8. Incertain embodiments, the solvate is a hydrate wherein the ratio of waterper molecule is within the range of from 1 to 6, i.e. a mono- tohexahydrate. In certain embodiments, it is a monohydrate or apentahydrate.

The terms “precipitating”/“precipitate”/“precipitation” in the contextof the present application shall encompass“crystallizing”/“crystallize”/“crystallization” unless stated otherwise.In certain embodiments, the precipitate described herein is amorphous.In certain embodiments, the precipitate is a mixture of amorphous andcrystalline components. In certain embodiments, the precipitatedescribed herein is crystalline. For example, 14-hydroxymorphinonesulfate may precipitate in a crystalline form during a process of thepresent invention.

The acronym “ppm” means parts per million. For purposes of the presentapplication, the numeric ppm amount values of opioids contained in acomposition containing more than one opioid are given in relation to theamount of the opioid (“reference opioid”) constituting the majority ofthe opioids contained in said composition. Such reference opioid willtypically be a compound of formula IV or a compound of formula II (whichmay be present in the composition as a structural moiety of compounds offormula V). The ppm values can be determined by performing achromatographic resolution of the composition and subsequent calculationof the relative or absolute amounts of the opioid components based onthe peak area. For purposes of the present invention, an HPLC method(e.g., as described in Example 12 for oxymorphone and its precursors)can be performed. The composition components can be detected at acertain wavelength (e.g., at 292 nm for oxymorphone and its precursors).The HPLC peak area ratio of a certain opioid component to the referenceopioid determines the ppm value. The numeric ppm amount value of the oneopioid compound constituting the majority of the opioids in thecomposition (i.e. of the reference opioid, which may be a compound offormula II or formula IV) can be obtained from the percent area of thepeak of this compound in relation to the area sum of all opioid peaks.

Under the HPLC conditions used in the context of the present invention(e.g., the HPLC conditions as described in Example 12 for oxymorphoneand its precursors; or any other reverse phase HPLC conditions), anysalt will not be determined in its salt form, but in a dissociated form.For example, the opioid moiety of a compound of formula V (e.g., of14-hydroxymorphinone sulfate) will be detected and quantified in itsdissolved form, i.e. as compound of formula II (e.g.,14-hydroxymorphinone). Consequently, the HPLC peak area detectable foran opioid salt of the present invention will be the HPLC peak area whichis detected for the opioid moiety comprised in said salt. In case a saltcontains more than one opioid moieties per anion, the HPLC method doesnot detect the absolute/relative amount of the salt itself, but of itsopioid moiety. If in such a salt two opioid moieties per anion arepresent (such as in a compound of formula V wherein n is 2), the peakarea detected in the HPLC is due to the presence of the two opioidmoieties contained in said salt. In case of a compound of formula Vwherein n is 3, the peak area detected in the HPLC is due to thepresence of the three opioid moieties contained in said compound offormula V.

This has the following consequence: As defined above, the numeric ppmvalue for an opioid is the ratio of peak area for said opioid inrelation to the peak area of the reference opioid. In case the presentapplication refers to numeric ppm values for a ratio of a compound offormula III to a compound of formula V, in fact the ratio of the peakarea for a compound of formula III to the peak area of the moietieshaving formula II (which are contained in the compound of formula V) isprovided. A compound of formula V comprises n-times the structural unitof formula II (e.g., two times for a sulfate salt, three times for aphosphate salt, etc.). All ppm values given in the description are basedon the original peak area ratio of the opioid moiety, without adjustingthem by dividing them by n. For example, if a peak area ratio of 4 ppmis determined via HPLC for a compound of formula V wherein n is 2, thecorresponding ppm value will also be 4 (and not 2). This way of givingcompound ratios in ppm will be designated as “HPLC peak area ratio” inthe following.

The opioid peaks which are typically considered in this determinationmethod are peaks having an UV-Vis spectrum which is typical for anopioid. In embodiments wherein a compound of formula V is14-hydroxymorphinone sulfate (or another 14-hydroxymorphinone salt orsolvate thereof) or a compound of formula IV is oxymorphone, typicallythe peaks of oxymorphone N-oxide, pseudo-oxymorphone (i.e.,2,2′-bisoxymorphone), 14-hydroxymorphine, 14-hydroxyisomorphine,10-ketooxymorphone, 14-hydroxymorphinone N-oxide, 10-hydroxyoxymorphone,8-hydroxyoxymorphone, 14-hydroxymorphinone, hydromorphone, oxymorphone,6α-oxymorphol (i.e., 14-hydroxydihydromorphine), 6β-oxymorphol (i.e.,14-hydroxydihydroisomorphine), oripavine, 8,14-dihydrooripavine,oxycodone (see, e.g., Example 12) may be considered (if present).However, not all of these peaks have to be considered. It is usuallysufficient to consider just some of them, for example10-hydroxyoxymorphone, 8-hydroxyoxymorphone, 14-hydroxymorphinone,oxymorphone, 6α-oxymorphol, and oripavine.

A reverse phase HPLC method may be used for determination of ppm values.

The detection of the sample components may be performed using a UV/VISdetector, e.g., at a wavelength of 292 nm.

Alternatively, the detection of the sample components may be performedusing a mass spectrometer. The amount of a certain component may bedetermined by using a tritiated internal standard. However, this methodof detection does not require the “HPLC peak area ratio” describedabove, as it uses an internal standard.

In the preferred embodiments, the HPLC method described in Example 12 isused for determination of ppm values. In one aspect of said embodiments,R¹ is —H. In one aspect of said embodiments, the compound of formula Vis 14-hydroxymorphinone sulfate and/or the compound of formula IV isoxymorphone.

In certain embodiments, an HPLC method described for an opioid in theUSP or European Pharmacopoeia is used for analysis of samples containingsaid opioid as component. For naloxone hydrochloride, this may be theHPLC method described in European Pharmacopoeia 01/2008:0729. Fornaltrexone hydrochloride, this may be the HPLC method described inEuropean Pharmacopoeia 01/2008:1790.

The acronym “ppb” means parts per billion.

The term “API” in the context of the present invention means “activepharmaceutical ingredient” (e.g., oxymorphone hydrochloride) and shallbe used in its broadest sense as a synonym for a pharmaceutically activecompound in the context of the present invention. When an API is used inpreparing a pharmaceutical composition or dosage form, the API is thepharmaceutically active component of said pharmaceutical composition ordosage form. Pharmaceutical compositions or dosage forms containing anAPI may be approved by a governmental agency for sale and use in apatient (e.g., a human). Examples of APIs described in the context ofthe present invention include, e.g., compounds of formula IV andpharmaceutically acceptable salts and solvates thereof, e.g.,oxymorphone or oxymorphone hydrochloride.

The term “pharmaceutical composition” in the context of the presentapplication means a composition which contains an API and is suitablefor use in a patient (e.g., a human). It may be approved by agovernmental agency for sale and use in a patient. Examples forpharmaceutical compositions described in the context of the presentinvention are among the compositions containing a compound of formula IVor a pharmaceutically acceptable salt or solvate thereof, e.g.,oxymorphone or oxymorphone hydrochloride. Pharmaceutical compositionsmay be compositions prepared according to the invention if they complywith regulatory requirements for pharmaceutical compositions containingthe same API.

The term “salt” in the context of the present application means acompound comprising at least one cation (e.g., one or two14-hydroxymorphinone cations resulting from protonation of14-hydroxymorphinone (free base) by a Bronsted acid (like sulfuricacid)) and at least one anion (e.g., a sulfate anion). A salt may be theresult of the neutralization reaction between an acid and a base (e.g.,a Bronsted acid and a Bronsted base, or a Lewis acid and a Lewis base).In its solid form, the salt may have a crystalline structure. The term“salt” as used in the present application includes anhydrous, solvated,or hydrated forms of the salt. Whenever a solution or mixture containinga salt is mentioned, the term “salt” shall also encompass the dissolvedform of the salt. The term also encompasses pharmaceutically acceptablesalts, in particular when it refers to a salt of a compound which canserve as API. In the context of present invention, whenever a14-hydroxymorphinone salt is mentioned, this refers to a salt containinga 14-hydroxymorphinone cation, resulting, e.g., from protonation of the14-hydroxymorphinone. The same applies to other salts containing acation with a morphine scaffold, e.g., a salt of an 8-hydroxy compoundwherein R¹ is —H. One example for a salt according to the presentinvention is a compound of formula V or a solvate thereof. An examplefor such compound of formula V is a salt which consists of two moleculesof 14-hydroxymorphinone and one molecule of H₂SO₄, i.e. which comprisestwo 14-hydroxymorphinone cations per sulfate anion (14-hydroxymorphinonesulfate). In this salt, the cation results from the protonation of twomolecules of 14-hydroxymorphinone and the anion is the resultingsulfate. In preferred embodiments of the present invention, a salt whichis a compound of formula V is in its solid form. Another example for asalt according to the present invention is a salt of a compound offormula IV or a solvate thereof. An example for such salt of a compoundof formula IV is a salt which consists of two molecules of oxymorphoneand one molecule of H₂SO₄, i.e. which comprises two oxymorphone cationsper sulfate anion (oxymorphone sulfate). In this salt, the cationresults from the protonation of two molecules of oxymorphone and theanion is the resulting sulfate. In preferred embodiments of the presentinvention, a salt of a compound of formula IV is in its solid form.

Whenever a compound or formula mentioned herein contains an atom orstructural element which could be a stereocenter (e.g., a chiral carbonatom or the morphine scaffold structure), it shall cover all possiblestereoisomers, unless indicated otherwise.

For compounds containing the morphine scaffold, the naturalstereoconfiguration of the morphine scaffold as shown in the followingshall be preferred:

wherein the degree of unsaturation in the ring formed by atoms 5, 6, 7,8, 14 and 13 may vary (the ring may, e.g., just contain single bonds asin compounds of formula III, or contain just one double bond as incompounds of formula II, or contain two double bonds as in compounds offormula I). At position 5, the following stereoconfiguration ispreferred (exemplified for the morphine scaffold of formula I):

For the 8-hydroxy compounds, an α or a β configuration is possible atposition 8 as illustrated in the following:

In the compounds and compositions of the present invention, either bothconfigurations or only one configuration at position 8 may be present.For the compounds of formula II, the following stereoconfigurationoccurs at position 14 as exemplified for 14-hydroxymorphinone in thefollowing:

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the auto-scaled chromatograph and peak results of theanalysis of the precipitated oxymorphone of Comparative Example 1.

FIG. 2 shows the auto-scaled chromatograph and peak results of theanalysis of the precipitated oxymorphone of Comparative Example 2.

FIG. 3 shows the auto-scaled chromatograph and peak results of theanalysis of the 14-hydroxymorphinone sulfate of Example 7 after thefirst filtration.

FIG. 4 shows the auto-scaled chromatograph and peak results of theanalysis of the 14-hydroxymorphinone sulfate of Example 7 after thesecond filtration.

FIG. 5 shows the auto-scaled chromatograph and peak results of theanalysis of the isolated solid 14-hydroxymorphinone sulfate of Example8.

FIG. 6 shows the auto-scaled chromatograph and peak results of theanalysis of the isolated solid 14-hydroxymorphinone sulfate of Example9.

FIG. 7 shows the auto-scaled chromatograph and peak results of theanalysis of the isolated solid oxymorphone of Example 10.

FIG. 8 shows a representative HPLC chromatogram for a standard mixtureof opioids resulting from the HPLC method of Example 12. Legend: seeExample 12.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of Formulae I, IL,III, IV and V

In the context of the present invention, compounds of formulae I, II,III, IV and V, and salts and solvates thereof, and mixtures of two ormore of any of the foregoing compounds are described. They may be usedas starting materials, intermediates or products of the processesaccording to present invention, or (e.g., compounds of formula V orsolvates thereof) may be themselves embodiments of the presentinvention. To these compounds, the following applies:

In all formulae,R¹ is —H, —(C₂-C₇)alkyl, aralkyl, —(C₂-C₆)alkenyl, —SiR³ ₃,—(C₃-C₇)cycloalkyl, —(C₁-C₇)alkyl-(C₃-C₇)cycloalkyl,—(C₃-C₇)cycloalkenyl, —(C₁-C₇)alkyl-(C₃-C₇)cycloalkenyl, —CR⁴₂—O—(C₁-C₆)alkyl, —C(halo)₃, —CH₂(halo), —CH(halo)₂, —SO₂R⁵, or anO-protecting group;R² is —H, —CH₃, —(C₂-C₇)alkyl, —(C₂-C₄)alkenyl, benzyl,—(C₁-C₇)alkyl-(C₃-C₇)cycloalkyl, —CN, or an N-protecting group;each R³ is independently selected from aryl, —(C₁-C₆)alkyl and—(C₁-C₆)alkoxy, preferably is —(C₁-C₄)alkyl or —(C₁-C₄)alkoxy, and morepreferably —SiR³ ₃ is trimethylsilyl (TMS), tert-butyldimethylsilyl(TBDMS), triethylsilyl (TES), or triisopropylsilyl (TIPS);each R⁴ is independently selected from —H and —(C₁-C₆)alkyl andpreferably is —H; andR⁵ is —(C₆-C₁₄)aryl or —(C₁-C₆)alkyl, preferably is —(C₁-C₄)alkyl, morepreferably is methyl or ethyl.

Preferably, R¹ and R² are independently of each other defined asfollows:

R¹ is —H, —(C₂-C₄)alkyl, benzyl, —(C₂-C₄)alkenyl, —SiR³ ₃,—(C₃-C₆)cycloalkyl, —(C₁-C₂)alkyl-(C₃-C₆)cycloalkyl,—(C₅-C₆)cycloalkenyl, —(C₁-C₃)alkyl-(C₅-C₆)cycloalkenyl, —CR⁴₂—O—(C₁-C₃)alkyl, —SO₂R⁵, or an O-protecting group; andR² is —H, —CH₃, —(C₂-C₄)alkyl, —(C₂-C₄)alkenyl, benzyl,—(C₁-C₃)alkyl-(C₃-C₆)cycloalkyl, —CN, or an N-protecting group.

More preferably, R¹ and R² are independently of each other defined asfollows: R¹ is —H, —(C₂-C₄)alkyl, benzyl, —(C₃)alkenyl, —SiR³ ₃,—(C₃-C₆)cycloalkyl, —(C₁-C₂)alkyl-(C₃-C₆)cycloalkyl,—(C₅-C₆)cycloalkenyl, —(C₁-C₃)alkyl-(C₅-C₆)cycloalkenyl, —CR⁴₂—O—(C₁-C₃)alkyl, —SO₂R⁵, or an O-protecting group; and

R² is —H, —CH₃, —(C₂-C₄)alkyl, —(C₃)alkenyl, benzyl,—(C₁-C₃)alkyl-(C₃-C₆)cycloalkyl, —CN, or an N-protecting group.

Even more preferably, R¹ and R² are independently of each other definedas follows:

R¹ is —H, ethyl, benzyl, allyl, or —CH₂-cyclopropyl; and R² is methyl,allyl, —CH₂-cyclopropyl, or —CH₂-cyclobutyl.

Most preferably, R¹ and R² are independently of each other defined asfollows:

R¹ is —H; and R² is methyl.

In all formulae containing stereocenters, any stereoconfiguration may bepresent, unless indicated otherwise. If a compound is the product of aprocess according to the present invention, those stereocenters of thestarting material which are not taking part in the reaction willmaintain their stereoconfiguration. In certain embodiments, thestereoconfiguration is as described in the Definitions section above.

In all formulae containing X^(n−), X^(n−) may be an inorganic or organicanion wherein n is 1, 2, or 3, preferably is 1 or 2, and more preferablyis 2.

X^(n−) may be any anion of a known opioid salt, including bromide,chloride, iodide, lactate, nitrate, acetate, tartrate, valerate,citrate, salicylate, meconate, barbiturate, HSO₄ ⁻, SO₄ ²⁻,methanesulfonate, tosylate, trifluoroacetate, H₂PO₄ ⁻, HPO₄ ²⁻, PO₄ ³⁻,oxalate, perchlorate, and any mixtures thereof.

Preferably, X^(n−) is selected from the group consisting of Cl⁻, HSO₄ ⁻,SO₄ ²⁻, methanesulfonate, tosylate, trifluoroacetate, H₂PO₄ ⁻, HPO₄ ²⁻,PO₄ ³⁻, oxalate, perchlorate, and any mixtures thereof. More preferably,X^(n−) is HSO₄ ⁻, SO₄ ²⁻, methanesulfonate, tosylate, trifluoroacetate,or a mixture thereof. Even more preferably, X^(n−) is HSO₄ ⁻, SO₄ ²⁻,methanesulfonate or trifluoroacetate. Even more preferably, X^(n−) isHSO₄ ⁻, SO₄ ²⁻, or trifluoroacetate. Even more preferably, X^(n−) isHSO₄ ⁻ or SO₄ ²⁻. Most preferably, X^(n−) is SO₄ ²⁻.

X^(n−) may be polymer-supported if n is 2 or 3.

Any combination of elements of these groups defined for R¹, R², R³, R⁴,R⁵, X^(n−) and n is also encompassed by the definitions of formulae I,II, III, IV and V.

In one embodiment of the processes of the present invention, thecompound of formula I is

or a salt or solvate thereof.

In a preferred embodiment, the compound of formula I is oripavine; thecompound of formula II is 14-hydroxymorphinone; the compound of formulaIII is 8α-hydroxyoxymorphone, 8β-hydroxyoxymorphone or a mixturethereof; and the compound of formula IV is oxymorphone or a saltthereof.

Oripavine may be contained in a concentrate of a poppy straw comprisingoripavine as a main alkaloid (CPS-O), or it may be purified oripavine,oripavine obtained from a botanical source, synthetic oripavine,semi-synthetic oripavine, oripavine bioengineered by, e.g., bacteria orplant cell cultures, or a combination of two or more of any of theforegoing.

The compound of formula V is preferably

or a solvate (e.g., a hydrate) thereof, respectively. As alreadymentioned above, this compound will in the context of the presentinvention be designated as 14-hydroxymorphinone sulfate. Because of itsstoichiometric composition, it may also be designated asbis(14-hydroxymorphinone)sulfate. The terms (compound of formulaII)sulfate (e.g., 14-hydroxymorphinone sulfate) and bis(compound offormula II)sulfate (e.g., bis(14-hydroxymorphinone)sulfate) are usedinterchangeably in the context of the present invention.

When a solvate of a compound of formula V is addressed, it may be anyassociation product of a compound of formula V with a solvent molecule.The molar ratio of solvent molecule(s) per molecule of formula V mayvary. The molar ratio of solvent to compound/salt in the solvate may be1 (e.g., in a monohydrate), more than 1 (e.g., 2, 3, 4, 5 or 6 in apolyhydrate), or less than 1 (e.g., 0.5 in a hemihydrate). The molarratio need not be an integer ratio, it can also be, e.g., 0.5 (as in ahemihydrate) or 2.5. For example, 1 molecule water per molecule of14-hydroxymorphinone sulfate is bound in 14-hydroxymorphinone sulfatemonohydrate. The solvate of the compound of formula V is in certainembodiments a hydrate, for example a monohydrate, dihydrate, trihydrate,tetrahydrate, pentahydrate or hexahydrate, or a hydrate wherein theratio of water per molecule is not necessarily an integer, but withinthe range of from 0.5 to 10.0. In certain embodiments, the solvate ofthe compound of formula V is a hydrate wherein the ratio of water permolecule is within the range of from 1 to 8. In certain embodiments, thesolvate of the compound of formula V is a hydrate wherein the ratio ofwater per molecule is within the range of from 1 to 6, i.e. a mono- tohexahydrate. In certain embodiments, the solvate of the compound offormula V is a monohydrate or a pentahydrate. The same applies to othersolvates in the context of the present invention, e.g. solvates of acompound of formula IV or of a salt thereof.

II. Processes for Preparing a Compound of Formula V

The present invention provides a process for preparing a compound offormula V or a solvate thereof from a compound of formula I or a salt orsolvate thereof, the process comprising:

(a) oxidizing the compound of formula I;(b) adding an acid H⁺ _(n)X^(n−) to the reaction mixture before, duringand/or after the oxidation reaction, thereby forming the compound offormula V.

This process is represented in the following reaction Scheme 9:

wherein R¹, R², X^(n−) and n are defined as above.

The compound of formula V formed by this process may further contain anamount of a compound of formula III. The amount of the compound offormula III formed during this process may be less than the amount ofthe compound of formula III formed during an oxidation of the compoundof formula I to the compound of formula II which does not involveformation of a compound of formula V.

As described above, the compound of formula III may be converted to thecompound of formula II during further processing of the compound offormula V to a compound of formula IV or a salt or solvate thereof. Ifless compound of formula III is formed according to the presentinvention, less compound of formula III and ultimately less compound offormula II may finally be present in a compound of formula IV or(optionally pharmaceutically acceptable) salt or solvate thereof (e.g.,oxymorphone or oxymorphone hydrochloride) made via or from the compoundof formula V or a solvate thereof, as compared to a compound of formulaIV or salt or solvate thereof made via a different intermediate. Lesscompound of formula III and ultimately less compound of formula II maythen also finally be present in a pharmaceutical composition or dosageform containing said compound of formula IV or a pharmaceuticallyacceptable salt or solvate thereof. Ultimately, the oxidation process ofthe present invention may therefore contribute to the result that theamount of the compounds of formula III and compounds of formula IIformed during preparation of a compound of formula IV or salt or solvatethereof is insufficient to increase the total amount of the compound(s)of formula II in said compound of formula IV above an undesired level,e.g., above a desired threshold amount of the compound of formula II.

Optionally, the compound of formula III may be separated from thecompound of formula V.

In certain embodiments, the oxidation step (a) is partially orcompletely performed in the presence of the acid H⁺ _(n)X^(n−) in thereaction mixture. That is, the acid H⁺ _(n)X^(n−) is added before orduring the oxidation reaction, preferably before the oxidation reaction.The acid H⁺ _(n)X^(n−) is preferably present in the reaction mixtureduring the complete oxidation reaction, i.e. it is added before thestart of the oxidation reaction, or at the start of the oxidationreaction.

The compound of formula V may precipitate in certain embodiments of thepresent invention.

The formation of the compound of formula V or solvate thereof may occurvia a salt formed from the compound of formula I, via a compound offormula II in its free base form or in its salt or solvate form, viaboth of said routes, or via a combination of one or both of said routeswith other reaction routes known to a person skilled in the art. By wayof example, the route via a compound of formula II in its free base formis shown in the following Scheme 10:

wherein R¹, R², X^(n−) and n are defined as above.

A variation of the route shown in Scheme 10 is a route wherein at leasta part or all of the compounds of formula I and/or formula II areprotonated. This may happen, e.g., under acidic reaction conditions.

In certain embodiments of the present invention, the formation of thecompound of formula V or a solvate thereof in this process allows for amore volume efficient oxidation of the compound of formula I incomparison to a process wherein no compound of formula V is formed.

In certain embodiments of this process, the formation of the compound offormula V results in a lower ratio of the compound of formula III to thecompound of formula II in the product, as compared to a process whereinno compound of formula V or solvate thereof is formed.

In certain embodiments of this process, said result may be achievedbecause the formation of the compound of formula V or a solvate thereofhas the effect that less 8-hydroxy compound of formula III is formedduring the oxidation reaction in comparison to an oxidation reactionwhere no compound of formula V or solvate thereof is formed. In otherwords, the formation of the compound of formula V allows for animprovement of the by-product profile of the reaction product.

In these embodiments, the oxidation reaction is typically completely orpartially performed in the presence of the acid H⁺ _(n)X^(n−).

One example for such embodiment may be the formation of a compound offormula V, wherein n is 2 and preferably wherein X^(n−) is sulfate.Another example for such embodiment may be the formation of a compoundof formula V, wherein n is I and preferably wherein X^(n−) istrifluoroacetate. Another example for such embodiment may be theformation of a compound of formula V, wherein n is 3 and preferablywherein X^(n−) is phosphate.

In certain embodiments of this process said result may be achievedbecause the formation of formula V or a solvate thereof has the effectthat compounds of formula III can be separated from the compound offormula V or the solvate thereof, e.g., by precipitation of the compoundof formula V or the solvate thereof from the reaction mixture. Oneexample for such an embodiment may be the formation of a compound offormula V wherein X^(n−) is sulfate.

In certain embodiments a combination of these effects takes place, i.e.,said result is achieved because both less compounds of formula III areformed during the oxidation and because said compounds of formula IIIcan be separated from the compound of formula V or solvate thereof. Oneexample for such an embodiment may be the formation of a compound offormula V wherein X^(n−) is sulfate.

Preferably, the formation of the compound of formula V or a solvatethereof reduces the formation of 8-hydroxy compounds of formula IIIduring the oxidation reaction and/or the presence of 8-hydroxy compoundsof formula III in the oxidation product, as compared to an oxidationreaction which does not involve the step of forming the compound offormula V or a solvate thereof. The presence of a compound of formulaIII in the product may be reduced by precipitation of the compound offormula V. This may reduce the formation of compounds of formula IIduring subsequent reactions (e.g., during conversion of oxymorphone madefrom a compound of formula V to oxymorphone hydrochloride), as comparedto reactions which do not involve the step of forming the compound offormula V or a solvate thereof.

The formation of the compound of formula V or a solvate thereof may alsoprovide an opportunity to perform additional steps at this stage tofurther lower the amount of an 8-hydroxy compound in the compound offormula V or solvate thereof, thereby reducing the amounts of compoundof formula II which may be potentially formed from the 8-hydroxycompound during a subsequent conversion of the compound of formula V,e.g., during a conversion to oxymorphone hydrochloride. These additionalsteps may comprise hydrogenation, heat treatment, (re)crystallization,washing the compound of formula V with a solvent which preferentiallyremoves the 8-hydroxy compound rather than the compound of formula V orthe solvate thereof, or any combinations of the foregoing.

The process for preparing the compound of formula V or a solvate thereofaccording to present invention may be performed by oxidizing a compoundof formula I with an oxidizing agent in the presence of one or moreacids such that the compound of formula V is formed. An 8-hydroxycompound of formula III or a salt or solvate thereof may be formed asby-product during the oxidation. At the end of the preparation of thecompound of formula V or a solvate thereof, said compound of formula Vor solvate thereof may be provided as a solid, a solution, or asuspension. The compound of formula V or a solvate thereof is anembodiment of the present invention, on its own right and in itsfunction as a starting material or intermediate for further processes ofthe present invention, e.g., processes for preparing an opioid offormula IV or an (optionally pharmaceutically acceptable) salt orsolvate thereof. The compound of formula V and the solvate thereof willbe described in more detail below. However, the subsequent descriptionof the processes of the present invention shall also apply to thecompound of formula V and the solvate thereof per se where applicable(e.g., when the compound of formula V is described as a reaction productof a process according to the invention).

In one aspect, the present invention provides a process for preparing acompound of formula V or solvate thereof which is a salt of14-hydroxymorphinone (as compound of formula II) from oripavine (ascompound of formula I), the resulting salt of 14-hydroxymorphinone(i.e., the compound of formula V), and processes for further conversionof the salt to compounds of formula IV or salts or solvates thereof, inparticular to oxymorphone or oxymorphone hydrochloride, or other opioidsby one or more further chemical reactions. The process according to thepresent invention for preparing said compound of formula V is depictedin the following Scheme 11:

In certain embodiments of this process, the acid H⁺ _(n)X^(n−) issulfuric acid.

The process for preparing a compound of formula V may be performed asone-pot-reaction, wherein steps (a) and (b) are performed concomitantly.Such one-pot-reaction is represented in Scheme 12:

In said one-pot-reaction, at least a part of the acid H⁺ _(n)X^(n−) istypically added before the oxidizing agent, or concomitantly with theoxidizing agent. In certain embodiments, all of the acid H⁺ _(n)X^(n−)is added before the oxidizing agent, or concomitantly with the oxidizingagent.

An exemplary one-pot reaction for forming a compound of formula V,namely 14-hydroxymorphinone sulfate, is depicted in Scheme 13:

In the oxidation reaction depicted in this Scheme, a peracid formed fromhydrogen peroxide and formic acid is used as at least one oxidizingagent, and sulfuric acid is used as the acid H⁺ _(n)X^(n−). It should benoted that it is not excluded that at least part of the sulfuric acidalso forms a peracid in the presence of the hydrogen peroxide, whichperoxide may also take part in the oxidation reaction.

The reaction conditions of steps (a) and (b) (e.g., time, temperature,pH, relative proportions of the reagents) will be described in detail inthe following. In a typical embodiment of the present invention, theyare adjusted such that the resulting product containing the compound offormula V is free from, or contains about 2500 ppm or less, 2000 ppm orless, about 1500 ppm or less, about 1000 ppm or less, about 500 ppm orless, or about 100 ppm or less of a 8-hydroxy compound of formula III.

Oxidation Reaction

The oxidation reaction of step (a) of the process according to presentinvention is represented in Scheme 14 and results in the formation ofthe structural moiety of formula II, which in turn is part of thecompound of formula V (the compound of formula II is depicted in squarebrackets in Scheme 14):

The oxidation reaction of step (a) is generally run until at least about90%, about 92%, about 95%, about 97%, about 98%, about 99% or about 100%of the compound of formula I is consumed by the reaction. The amount ofsaid compound remaining in the reaction may be determined by anyconventional determination method, e.g., by HPLC, for example the HPLCmethod described in Example 12.

The oxidizing reaction time can be anywhere from about 1 minute to about36 hours, from about 10 minutes to about 34 hours, from about 20 minutesto about 32 hours, from about 30 minutes to about 30 hours, from about45 minutes to about 28 hours, from about 1 hour to about 24 hours, fromabout 3 hours to about 21 hours, from about 5 hours to about 18 hours.In certain embodiments, the reaction time is about 30 minutes, about 1hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours,about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours,about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about24 hours.

The reaction mixture may be maintained at a temperature of from about 0°C. to about 100° C., from about 10° C. to about 90° C., from about 15°C. to about 80° C., from about 20° C. to about 70° C., from about 20° C.to about 60° C., from about 20° C. to about 55° C., from about 20° C. toabout 45° C., from about 20° C. to about 40° C., or from about 20° C. toabout 35° C.

In certain embodiments, e.g., in a reaction conducted in a flow reactor,the reaction mixture may be maintained at a temperature as listed in thepreceding sentence, or it may be maintained at a temperature exceedingsome of the upper temperature limits of the preceding sentence, e.g., ata temperature of from about 40° C. to about 95° C.

In certain embodiments, the reaction mixture is maintained at from about20° C. to about 45° C., preferably from about 25° C. to about 40° C. Incertain embodiments, the reaction mixture is maintained more preferablyat from about 25° C. to about 35° C., even more preferably at about 30°C. In certain especially preferred embodiments, the reaction mixture ismaintained more preferably at from about 30° C. to about 38° C., morepreferably at at from about 32° C. to about 36° C., even more preferablyat about 35° C. Typically, the oxidation reaction will be finished afterabout 24 hours or even less hours (e.g., 16 or 20 hours) when thesepreferred temperatures are used.

Typically, the oxidation of the compound of formula I during step (a) istaking place in the presence of an oxidizing agent. Said oxidizing agentis either added to the reaction mixture, or it is formed in situ in thereaction mixture (e.g., performic acid may be formed in situ in areaction mixture comprising formic acid and hydrogen peroxide). Thecompound of formula I is then oxidized to the compound of formula V,which will result when the acid H⁺ _(n)X^(n−) is present.

The compound of formula I may be provided for step (a) in a solution orsuspension comprising the compound of formula I and a suitable solvent.A suitable solvent may comprise or consist of water; an alcohol (e.g.,methanol, ethanol, n-propanol, isopropanol, 1-butanol, 2-butanol,isobutanol, tert-butanol, tert-amyl alcohol, 2-ethoxyethanol,1-methoxy-2-propanol, etc.); an aromatic hydrocarbon (e.g., benzene,toluene, xylol, etc.); an ether (e.g., 1,4-dioxane, tetrahydrofuran,2-methyl-tetrahydrofuran, diethylether, tert-butyl methyl ether, etc.);a (C₁-C₄) alkyl ester of a (C₁-C₄) alkanoic acid (e.g., methyl formate,methyl acetate, ethyl acetate, isopropyl acetate, etc.); an amide (e.g.,dimethylformamide, diethylformamide, dimethylacetamide, or otherN—(C₁-C₄) alkyl substituted (C₁-C₄) alkanoic acid amides);N-methylpyrrolidone; formylmorpholine; or any mixtures of any of theforegoing. In certain embodiments, the reagent providing an acid for theprocess (e.g., 88% formic acid in water), or the acid itself can act assolvent. In certain embodiments, the solvent comprises or consists ofwater, an ether, an alcohol, or a combination thereof. In certainembodiments, the solvent comprises, or consists of methanol,tetrahydrofuran, n-propanol, isopropanol, 1-butanol, 2-butanol,isobutanol, tert-butanol, acetone, ethanol, 1-methoxy-2-propanol,2-ethoxyethanol, tert-amyl alcohol, or a mixture of water with any oneof the foregoing. In certain embodiments, the solvent comprises orconsists of tetrahydrofuran, isopropanol, methanol, ethanol, 1-butanol,2-butanol, isobutanol, tert-butanol, tert-amyl alcohol, n-propanol orany combination thereof. In certain embodiments, the solvent is water ora combination of water with another solvent. In certain embodiments, thesolvent is isopropanol or a mixture of isopropanol and water. In certainembodiments, the solvent is 2-butanol or a mixture of 2-butanol andwater. In certain other embodiments, the solvent is free orsubstantially free from water (e.g., when the reaction is performed inchloroform using MCPBA as oxidizing agent). In certain preferredembodiments, the solvent comprises or consists of water.

The ratio of the compound of formula I to the solvent is selected suchthat the compound of formula I is dissolved in the solvent, i.e. suchthat a suspension or preferably a solution of the compound of formula Iis formed. If the oxidizing agent contains or is generated with an acidwhich acts as a solvent (e.g., formic acid), or if the acid H⁺_(n)X^(n−) acts as a solvent, said acid contributes to the total amountof solvent in the reaction mixture or is the sole solvent in thereaction mixture. The ratio of the compound of formula I (in mmol) tothe solvent (in mL) may be defined as molarity by the following formula:

molarity=(mmol of compound of formula I)/(milliliters of solvent).

For example, when 33.7 mmol of compound 1 and 23.6 ml water plus formicacid are used, this results in a molarity of 1.43 (33.7/23.6). In thepresent invention, the molarity of the compound of formula I in relationto the solvent is preferably ≧0.8. In certain embodiments, the molarityis from 0.8 to 1.8, preferably from 1.2 to 1.7, more preferably from 1.2to 1.6 and even more preferably from 1.3 to 1.5. In comparison, in WO2008/130553, the molarity is 0.67 ((10 mmol compound of formula I)/(15ml water plus formic acid)). The less solvent is used, the more volumeefficient steps (a) and (b) may be if the process yield remainsconstant. Thus, the present invention provides a process which allowsfor the use of less solvent, which in turn may reduce the environmentalburden and/or production costs.

In certain embodiments, the solvent comprises or consists of water, e.g.in the embodiments described in the Examples. The ratio of the compoundof formula I (in mmol) to water (in ml) in said embodiments ispreferably from about 1:1 to about 5:1, more preferably from about 1.2:1to about 4:1, more preferably from about 1.5:1 to about 3:1, morepreferably from about 1.6:1 to about 2.4:1, even more preferably fromabout 1.7:1 to about 2.2:1. E.g., in a preferred embodiment, from about1.5 ml to about 2.0 ml, preferably from about 1.6 to about 1.9 ml waterper g oripavine are used. This calculation does not take into accountwater contained in one of the acids or other reagents (in particular,hydrogen peroxide) used in the oxidation reaction.

Before the oxidation reaction is initiated (e.g., by adding orgenerating an oxidizing agent), the compound of formula I may be presentin any percentage of the reaction mixture. In certain embodiments, it ispresent in a starting amount of from about 1% to about 60%, from about5% to about 50%, from about 10% to about 40%, from about 15% to about35%, from about 20 to about 33%, or from about 20% to about 30% perweight of the complete reaction mixture. In certain preferredembodiments, the compound of formula I comprises from about 20 to about33% of the reaction mixture by weight. In certain preferred embodiments,the compound of formula I comprises from about 20% to about 30% of thereaction mixture by weight. As the oxidation takes place, theconcentration of the compound of formula I decreases and may finallyapproach 0%.

The oxidizing agent may be a peracid, a peroxide (which encompasseshydrogen peroxide and peroxide salts), a periodinane, singlet oxygen orany combination thereof. For example, an oxidizing agent may be hydrogenperoxide, potassium peroxymonosulfate (e.g., OXONE®), performic acid,peracetic acid (AcOOH), persulfuric acid, m-chloroperoxybenzoic acid(MCPBA), trifluoro peracetic acid, singlet oxygen, iodosylbenzene, K₂O₂,Na₂O₂, Li₂O₂, Cs₂O₂, Cs₂O₂, K₂SO₅, NaSO₅, or an appropriate mixture ofany two or more of the foregoing. Said oxidizing agent may be eithergenerated in situ in the reaction mixture (e.g., performic acid fromhydrogen peroxide and an acid), or it may be added to the reactionmixture (e.g., MCPBA).

In certain embodiments, the oxidizing agent is a peracid. Said peracidmay either be generated in situ in the reaction mixture from hydrogenperoxide and an acid or from another combination of reagents leading tothe formation of a peracid (e.g., from a peroxide salt and an acid), orit may be added to the reaction mixture (e.g., MCPBA, or a peracidgenerated ex situ, i.e. separately from the reaction mixture before itsaddition to the reaction mixture). If the peracid is generated in situ,the peroxide may be added after the acid and/or at a pH of the reactionmixture which is less than 7.

In certain embodiments, the peracid may be performic acid, peraceticacid, MCPBA, potassium peroxymonosulfate (which contains one peracidgroup), trifluoro peracetic acid, persulfuric acid, or a combination ofany two or more thereof. When said peracid is generated in situ, thecorresponding starting acid is formic acid, acetic acid, 3-chlorobenzoicacid, potassium monosulfate, trifluoroacetic acid, sulfuric acid, or amixture of any two or more of the foregoing.

In certain embodiments, the peracid comprises or is performic acid. Whenthe performic acid is generated in situ or ex situ, it is in oneembodiment generated from formic acid and hydrogen peroxide.

In certain embodiments, the peracid comprises or is a combination ofperformic acid and persulfuric acid. When said combination is generatedin situ or ex situ, it is in one embodiment generated from formic acid,sulfuric acid and hydrogen peroxide.

In certain embodiments, the oxidizing agent is or is generated fromhydrogen peroxide (e.g., added to the reaction mixture in 5, 10, 15, 20,25, 30, 35, 40, 45, 50, 60, or 70% aqueous solution). In certainembodiments, 35% aqueous solution of hydrogen peroxide is added to thereaction mixture. In certain embodiments, at the beginning of thereaction, hydrogen peroxide may comprise about 8-10% of the reactionmixture by volume, and, as the oxidation reaction takes place, theconcentration of hydrogen peroxide decreases and may even reach 0%.

In general, the oxidizing agent, e.g., a peracid generated from an acidand hydrogen peroxide, is present in an amount of from about 0.8 toabout 5 moles per mole of the compound of formula I. In certainembodiments, from about 1 to about 2 moles of the oxidizing agent per 1mole of the compound of formula I are utilized. In certain embodiments,about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about1.6, about 1.8, or about 1.9 moles of the oxidizing agent per mole ofthe compound of formula I are used. In certain embodiments, from about 1to about 1.6 moles of the oxidizing agent per mole of the compound offormula I are utilized. In certain embodiments, from about 1 to about1.4 moles of the oxidizing agent per mole of the compound of formula Iare utilized. In certain embodiments, from about 1.2 to about 1.4 molesof the oxidizing agent per mole of the compound of formula I areutilized. In certain embodiments, from about 1.2 to about 1.3 moles(e.g., 1.25 molar equivalents) of the oxidizing agent per mole of thecompound of formula I are utilized. In certain embodiments, from about 1to about 1.25 moles of the oxidizing agent per mole of the compound offormula I are utilized. In certain embodiments, from about 1.05 to about1.15 moles (e.g., 1.05 molar equivalents) of oxidizing agent per mole ofthe compound of formula I are used. In embodiments wherein a peracid isgenerated in situ, the molar amount of the starting component containingthe peroxy group (e.g., hydrogen peroxide) is deemed to represent themolar amount of the resulting peracid in the reaction mixture.

In those embodiments wherein the oxidizing agent is a peracid generatedin situ from hydrogen peroxide and an acid in the reaction mixture,preferably from about 1 to about 1.6 moles of hydrogen peroxide per moleof the compound of formula I are utilized. In certain embodiments, fromabout 1 to about 1.5 moles of hydrogen peroxide per mole of the compoundof formula I are utilized. In certain embodiments, from about 1.2 toabout 1.4 moles of hydrogen peroxide per mole of the compound of formulaI are utilized. In certain embodiments, from about 1.2 to about 1.3moles (e.g., 1.25 molar equivalents) of the oxidizing agent per mole ofthe compound of formula I are utilized. In certain embodiments, fromabout 1 to about 1.25 moles of hydrogen peroxide per mole of thecompound of formula I are utilized. In certain embodiments, from about1.05 to about 1.15 moles (e.g., 1.05 molar equivalents) of hydrogenperoxide per mole of the compound of formula I are used.

In a preferred embodiment, from about 1 to about 1.5 moles of theoxidizing agent per mole of the compound of formula I are utilized, andmore preferably, especially in cases where full conversion shall beachieved within about 24 hours or less, from about 1.2 to about 1.5moles or from about 1.2 to about 1.4 moles of the oxidizing agent permole of the compound of formula I are utilized. This means that in saidpreferred embodiment, when the oxidizing agent is a peracid generated insitu from hydrogen peroxide and an acid in the reaction mixture, fromabout 1 to about 1.5 moles of hydrogen peroxide per mole of the compoundof formula I are utilized, and more preferably, from about 1.2 to about1.4 moles of hydrogen peroxide per mole of the compound of formula I areutilized. In a particular aspect of said preferred embodiment, fromabout 1.2 to about 1.3 moles (e.g., about 1.25 moles) of hydrogenperoxide per mole of the compound of formula I are utilized. In saidpreferred embodiment, the compound of formula I is in one aspect of theinvention oripavine.

In those embodiments wherein the oxidizing agent is a peracid generatedin situ from hydrogen peroxide and an acid in the reaction mixture, theacid for generating the peracid preferably is or comprises formic acid.This also encompasses processes wherein the peracid is generated from acombination of formic acid and sulfuric acid.

The molar amount of an acid used for generating a peracid in situ may beless than, equal to, or exceeding the molar amount of the compound offormula I. In certain embodiments, an excess of said acid over theamount of the compound of formula I will be utilized. In certainembodiments, said acid is used in excess over the amount of the peroxide(e.g., hydrogen peroxide) which is used to generate the peracid. Incertain embodiments, the amount of the acid used for generating theperacid (e.g., of formic acid) is from about 0.5 to about 14 molarequivalents per molar equivalent of the compound of formula I,preferably from about 1 to about 12 molar equivalents, more preferablyfrom about 1 to about 7 molar equivalents, more preferably from about1.5 to about 6 molar equivalents, more preferably from about 2 to about5 molar equivalents, more preferably from about 2.5 to about 4.5 molarequivalents, even more preferably from about 2.5 to 4 molar equivalentsper molar equivalent of the compound of formula I.

In a specific aspect of the invention, the molar amount of the acid usedfor generating the peracid in situ is from about 2.5 to about 4.5equivalents per molar equivalent of the compound of formula I, and themolar amount of the peroxide is from about 1 to about 1.5 moles,preferably from about 1.2 to about 1.4 moles, more preferably from about1.2 to about 1.3 moles per mole of the compound of formula I. In saidaspect, the acid is preferably formic acid, and the peroxide ispreferably hydrogen peroxide.

When an acid is used for generating the oxidizing agent in situ, twoacids may be used during a process encompassing steps (a) and (b): afirst acid (which is used to generate at least a part of the peracid insitu in step (a)), and a second acid (which is the acid H⁺ _(n)X^(n−) ofstep (b), which in certain embodiments may also generate a part of theperacid in situ in step (a)). The second acid may be added before,simultaneously with, or after addition of the first acid. In certainembodiments, the acids are pre-mixed and the pre-mixture is added to thesolution or suspension. In certain embodiments, the first acid and thesecond acid may each be independently added all at once or in dividedportions. In certain embodiments, the first acid is formic acid and thesecond acid is sulfuric acid.

The acid H⁺ _(n)X^(n−) of step (b) may be added as acid H⁺ _(n)X^(n−) ormay be generated in situ in the reaction mixture from a salt containingan anion X^(n−).

The acid H⁺ _(n)X^(n−) may be added (or generated in situ) before,during or after the oxidation reaction of step (a), or at anycombination of these time points. It may be added once, in severalbatches or continuously over a certain period of time. It may be addedat or during several points in time in relation to the oxidationreaction, e.g., before, during and after the oxidation, or before andduring the oxidation reaction. If it is added (or generated) beforeand/or during the oxidation reaction, the process comprising steps (a)and (b) is performed as a one-pot-reaction. Said one-pot-reaction may bemore cost-, time- and/or volume-efficient and may therefore bepreferred. Especially preferred is a process wherein the acid H⁺_(n)X^(n−) is added to (or generated in) the reaction mixture before theoxidation reaction of step (a).

In certain embodiments, a portion or all of the acid H⁺ _(n)X^(n−) addedafter some or substantially all of the compound of formula I has beenoxidized. In certain embodiments, H⁺ _(n)X^(n+) is added aftersubstantially all of the compound of formula I has been consumed, withthe proviso that the acid H⁺ _(n)X^(n−) is not hydrochloric acid inthese embodiments, preferably with the proviso that the acid H⁺_(n)X^(n−) is not methanesulfonic acid, sulfuric acid, phosphoric acidor hydrochloric acid in these embodiments.

In certain embodiments, step (b) of the process is performed by addingH⁺ _(n)X^(n−) (e.g., H₂SO₄) to the reaction mixture.

H⁺ _(n)X^(n−) may be any acid containing an anion X^(n−) as definedherein. It may, for example, be HCl, H₂SO₄ or its monosalt,methanesulfonic acid, tosylic acid, trifluoroacetic acid, H₃PO₄ or oneof its mono- or disalts, oxalic acid, perchloric acid, or any mixturesthereof. In certain embodiments, it may be HCl, H₂SO₄, methanesulfonicacid, tosylic acid, trifluoroacetic acid, or a mixture thereof. Incertain embodiments, it is H₂SO₄, methanesulfonic acid, ortrifluoroacetic acid or a mixture thereof. In certain embodiments, it istrifluoroacetic acid. In certain embodiments, it is H₂SO₄. In certainembodiments, it is methanesulfonic acid.

H⁺ _(n)X^(n−) may in certain embodiments be polymer supported if n is 2or 3.

The molar amount of H⁺ _(n)X^(n−) present in step (b) may be the same asor different from the molar amount of the compound of formula I providedfor step (a). For example, in embodiments wherein n is 2, the salt oracid added in step (b), e.g., H₂SO₄ or a salt thereof, may be added inan amount of from about 0.1 to about 1.5 molar equivalents, preferablyof from about 0.1 to about 1.2 molar equivalents, more preferably offrom about 0.1 to about 1 molar equivalents', even more preferably offrom about 0.25 to about 0.75 molar equivalents, even more preferably offrom about 0.4 to about 0.6 molar equivalents, even more preferably offrom about 0.45 to about 0.55 molar equivalents or from about 0.5 toabout 0.6 molar equivalents per molar equivalent of the compound offormula I. In certain embodiments wherein n is 2, the salt or acid addedin step (b), e.g., H₂SO₄ or a salt thereof, is added in an amount ofabout 0.5 to about 0.6 equivalents, e.g. of about 0.51 to about 0.55molar equivalents per molar equivalent of the compound of formula I.

In certain embodiments, the amount of H⁺ provided by H⁺ _(n)X^(n−) instep (b) is in a slight molar excess in comparison to the compound offormula I. In certain embodiments, the molar amount of H⁺ _(n)X^(n−)present in step (b) is within a range of about 1/n+10% to about 1/n+20%molar equivalents per one molar equivalent of the compound of formula I.

In certain embodiments, the acid H⁺ _(n)X^(n−) is the only acid usedduring the process encompassing steps (a) and (b). In those embodimentswhere a peracid is used as oxidizing agent, said acid H⁺ _(n)X^(n−) iscapable to form a peracid and will be used for generating said peracid.

In certain other embodiments, one or more additional acids are added tothe reaction mixture. In those embodiments where a peracid is used asoxidizing agent, there may be used an acid for generating the peracidwhich is different from the acid H⁺ _(n)X^(n−). This acid is then anadditional acid. In other embodiments, a further additional acid may beadded to the reaction mixture in addition to the acid H⁺ _(n)X^(n−) andthe acid for generating the peracid. Such further acid may be anyremaining acid selected from the acids defined as the acid H⁺ _(n)X^(n−)and as the acid for generating the peracid in the present description,or any mixture of said remaining acids.

The total amount of acid used during steps (a) and (b) of the process isimportant, because it may influence whether or not the compound offormula V precipitates from the reaction mixture during the process. Italso determines the amount of base which will be required aftercompletion of the reaction if a neutralization of the reaction mixtureis desired. The total amount of acid includes the acid H⁺ _(n)X^(n−)and, if present, the acid used for generating a peracid and any furtheracid added to the reaction mixture during steps (a) and (b). The totalamount of acid may range from about 0.6 to about 14.0 molar equivalentsof total acid per molar equivalent of the compound of formula I.

In certain embodiments, from about 1 to about 12 molar equivalents oftotal acid per molar equivalent of the compound of formula I are used.In certain embodiments, from about 1 to about 10, from about 1 to about8, from about 1 to about 7, from about 1 to about 6.5, from about 1 toabout 6, from about 1 to about 5.5, from about 1 to about 5, from aboutI to about 4.5, from about 1 to about 4, from about 1 to about 3.5, orfrom about 1.5 to about 3.5 molar equivalents of total acid per molarequivalent of the compound of formula I are used.

In certain embodiments, from about 1 to about 8 molar equivalents,preferably from about 1 to about 5 molar equivalents, more preferablyfrom about 1.5 to about 4.5 molar equivalents, even more preferably fromabout 3 to about 4 molar equivalents of total acid per molar equivalentof the compound of formula I are used.

In certain embodiments, from about 1.2 to about 4.5 molar equivalents oftotal acid per molar equivalent of the compound of formula I are used.

In certain embodiments, from about 2.5 to about 5.5 molar equivalents,preferably from about 3 to about 5 molar equivalents of total acid permolar equivalent of the compound of formula I are used.

In certain embodiments where an acid H⁺ _(n)X^(n−) and an acid used forgenerating the peracid (which is different from H⁺ _(n)X^(n−)) are used,the molar ratio of the acid H⁺ _(n)X^(n−) to the acid used forgenerating the peracid (e.g., of sulfuric acid to formic acid) is fromabout 1:20 to about 1:0.5, from about 1:17 to about 1:1, from about 1:15to about 1:1, from about 1:14 to about 1:1, from about 1:12 to about1:1, from about 1:10 to about 1:1, from about 1:9 to about 1:2, fromabout 1:8 to about 1:3, from about 1:7 to about 1:3, from about 1:7 toabout 1:5, or a numeric value lying within these ranges. In certainembodiments, the molar ratio of the acid H⁺ _(n)X^(n−) to the acid usedfor generating the peracid is from about 1:9 to about 1:4, preferablyfrom about 1:7.5 to about 1:4, more preferably from about 1:7 to about1:5, or a numeric value lying within these ranges.

In certain embodiments, from about 2.5 to about 4.5 molar equivalents ofthe acid used for generating a peracid per molar equivalent of thecompound of formula I are used, and from about 0.1 to about 1.5, fromabout 0.1 to about 1, from about 0.2 to about 0.9, from about 0.25 toabout 0.75, from about 0.4 to about 0.6, or from about 0.5 to about 0.6molar equivalents of the acid H⁺ _(n)X^(n−) per molar equivalent of thecompound of formula I are used. In said embodiments, said first acid maybe formic acid, and said second acid may be sulfuric acid.

In certain embodiments, from about 0.5 to about 4 molar equivalents ofthe acid used for generating a peracid per molar equivalent of thecompound of formula I are used, and from about 0.1 to about 1.5, fromabout 0.1 to about 1, from about 0.2 to about 0.9, from about 0.25 toabout 0.75, from about 0.4 to about 0.6, or from about 0.5 to about 0.6molar equivalents of the acid H⁺ _(n)X^(n−) per molar equivalent of thecompound of formula I are used. In said embodiments, said first acid maybe formic acid, and said second acid may be sulfuric acid.

In certain embodiments, from about 0.5 to about 3.5 molar equivalents ofthe acid used for generating a peracid per molar equivalent of thecompound of formula I are used, and from about 0.1 to about 1.5, fromabout 0.1 to about 1, from about 0.2 to about 0.9, from about 0.25 toabout 0.75, from about 0.4 to about 0.6, or from about 0.5 to about 0.6molar equivalents of the acid H⁺ _(n)X^(n−) per molar equivalent of thecompound of formula I are used. In said embodiments, said first acid maybe formic acid, and said second acid may be sulfuric acid.

In certain embodiments, from about 1 to about 3 molar equivalents of theacid used for generating a peracid per molar equivalent of the compoundof formula I are used, and from about 0.4 to about 0.6, or from about0.5 to about 0.6 molar equivalents of the acid H⁺ _(n)X^(n−) per molarequivalent of the compound of formula I are used. In said embodiments,said first acid may be formic acid, and said second acid may be sulfuricacid.

In a preferred embodiment utilizing formic acid and sulfuric acid, theoxidation is performed by oxidizing the compound of formula I in thepresence of about 12 molar equivalents or less, about 10 molarequivalents or less, about 8 molar equivalents or less, about 7 molarequivalents or less, about 6 molar equivalents or less, about 5 molarequivalents or less, about 4 molar equivalents or less, about 3 molarequivalents or less, about 2 molar equivalents or less, or about 1 molarequivalents (e.g., 1.05 molar equivalents) or less of total acid per onemolar equivalent of the compound of formula I, wherein from about 0.1 toabout 1.5 molar equivalents of total acid comes from the acid H⁺_(n)X^(n−). In one particular embodiment, the compound of formula I isoxidized to the compound of formula V by exposing each molar equivalentof the compound of formula I to (i) from about 1.0 to about 1.6,preferably from about 1.2 to about 1.4 molar equivalents of hydrogenperoxide, (ii) from about 0.3 to about 9, from about 0.5 to about 8,from about 0.5 to about 4.5, or from about 2.5 to about 4.5 molarequivalents of the acid used for generating the peracid, and (iii) fromabout 0.1 to about 1.5, from about 0.25 to about 0.9, or from about 0.4to about 0.6 molar equivalents of the acid H⁺ _(n)X^(n−). In certainembodiments, from about 2.5 to about 4 molar equivalents of the acidused for generating the peracid per one molar equivalent of the compoundof formula I are used. In certain embodiments, from about 0.4 to about0.6 molar equivalents of the acid H⁺ _(n)X^(n−), and from about 2.5 toabout 4 molar equivalents of the acid used for generating the peracidare used. In certain embodiments, from about 0.4 to about 0.6 molarequivalents of the acid H⁺ _(n)X^(n−), and from about 1 to about 3 molarequivalents of the acid used for generating the peracid are used. Incertain embodiments, from about 0.5 to about 0.6 molar equivalents ofthe acid H⁺ _(n)X^(n−), and from about 2.5 to about 4.5 molarequivalents of the acid used for generating the peracid are used. Incertain embodiments, conducting the oxidation reaction under theseconditions may improve the volume efficiency of the reaction and mayreduce the number and amounts of by-products formed during the oxidationreaction.

In certain embodiments, a portion or all of the H⁺ _(n)X^(n−) (e.g.,H₂SO₄) is added to the reaction mixture before the acid or the peroxideused for generating the peracid is added, or at the same point in time.

In certain embodiments, H⁺ _(n)X^(n−) (e.g., H₂SO₄) is added after theacid used for generating the peracid (e.g., formic acid). In certainembodiments, the reaction mixture may already comprise formic acid, andsulfuric acid is then added.

In preferred embodiments, the compound of formula V is precipitated fromthe reaction mixture, either because the presence of the acid H⁺_(n)X^(n−) (e.g., H₂SO₄) induces the precipitation of the compound offormula V or a solvate thereof during the oxidation reaction, or becausein addition to said presence the precipitation is started or enhanced byother measures, e.g., by adjusting the temperature of the solutionand/or adding a suitable antisolvent to the solution, as described inmore detail below. In certain embodiments, precipitation is achieved byadding a suitable antisolvent. In certain embodiments, precipitation isachieved by lowering the temperature below the reaction temperature ofthe oxidation reaction. The pH of the reaction mixture at this reactionstage is generally acidic (e.g., a pH of less than about 2). It istherefore unexpected that in the presence of the H⁺ _(n)X^(n−) in thereaction mixture precipitation of the compound of formula V or solvatethereof may take place.

The reaction steps (a) and (b) are typically performed in a solvent. Theamount of said solvent is described above with regard to molarity.

In certain embodiments, the oxidizing agent is or comprises performicacid generated, e.g., from hydrogen peroxide and formic acid, and thesolvent is water, an alcohol, a mixture of two or more alcohols, or amixture of an alcohol and water. The solvent may be methanol or amixture of methanol and water. The solvent may be isopropanol or amixture of isopropanol and water. The solvent may be water.

In certain embodiments, the oxidizing agent is or comprises performicacid and persulfuric acid generated, e.g., from hydrogen peroxide andformic acid and sulfuric acid, and the solvent is water, an alcohol, amixture of two or more alcohols, or a mixture of an alcohol and water.The solvent may be methanol or a mixture of methanol and water. Thesolvent may be isopropanol or a mixture of isopropanol and water. Thesolvent may be water.

In certain embodiments, the oxidizing agent is or comprises peraceticacid, and the solvent is water, an alcohol, a mixture of two or morealcohols, or a mixture of an alcohol and water.

In certain embodiments, the process is for preparing14-hydroxymorphinone (as compound of formula II) from oripavine (ascompound of formula I) and step (a) is performed with an oxidizing agentformed from an acid and hydrogen peroxide. In certain embodiments, theamount of total acid present in the reaction mixture is about 12 molarequivalents or less, about 10 molar equivalents or less, about 8 molarequivalents or less, about 7 molar equivalents or less, about 6 molarequivalents or less, about 5 molar equivalents or less, about 4 molarequivalents or less, about 3 molar equivalents or less, about 2 molarequivalents or less, or about 1 molar equivalents (e.g., 1.05 molarequivalents) or less per molar equivalent of oripavine. In oneparticular embodiment, the oripavine is oxidized to the14-hydroxymorphinone moiety of formula V or a solvate thereof byexposing each molar equivalent of the oripavine to from about 1.0 toabout 1.6, preferably from about 1.2 to about 1.4 molar equivalents ofhydrogen peroxide, from about 0.3 to about 9 molar equivalents, fromabout 0.5 to about 8 molar equivalents, or from about 2.5 to about 4.5molar equivalents of formic acid, and from about 0.4 to about 0.6 molarequivalents of sulfuric acid. In certain embodiments, from about 0.5 toabout 5 molar equivalents of formic acid per one molar equivalent oforipavine are used. In certain embodiments, from about 2.5 to about 4.5molar equivalents of formic acid per one molar equivalent of oripavineare used. In certain embodiments, from about 2.5 to about 4 molarequivalents of formic acid per one molar equivalent of oripavine areused.

In certain embodiments, the process is for preparing14-hydroxymorphinone (as compound of formula II) from oripavine (ascompound of formula I) and is performed by: (i) forming a solution or asuspension comprising oripavine and from about 1.5 to about 4 molarequivalents of a first acid (e.g., formic acid) per molar equivalent oforipavine, (ii) adding from about 0.4 to about 0.6 molar equivalents ofthe acid H⁺ _(n)X^(n−) (e.g., sulfuric acid) per molar equivalent oforipavine to the solution or the suspension, (iii) adding from about 1to about 1.6 molar equivalents of hydrogen peroxide to the solution orthe suspension from (ii), and (iv) precipitating the14-hydroxymorphinone salt of formula V from the solution or suspension(e.g., by adjusting the temperature of the solution and/or adding asuitable antisolvent to the solution, as described in more detailbelow). In certain embodiments, precipitation is achieved by adding asuitable antisolvent. In certain embodiments, precipitation is achievedby lowering the temperature below the reaction temperature of theoxidation reaction.

In certain embodiments, the process is for preparing14-hydroxymorphinone (as compound of formula II) from oripavine (ascompound of formula I) and is performed by: (i) forming a solution or asuspension comprising oripavine and from about 2.5 to about 4.5 molarequivalents of a first acid (e.g., formic acid) per molar equivalent oforipavine, (ii) adding from about 0.5 to about 0.6 molar equivalents ofthe acid H⁺ _(n)X^(n−) (e.g., sulfuric acid) per molar equivalent oforipavine to the solution or the suspension, (iii) adding from about 1.0to about 1.4 molar equivalents, preferably from about 1.2 to about 1.4molar equivalents, and more preferably from about 1.2 to about 1.3 molarequivalents of hydrogen peroxide to the solution or the suspension from(ii), and (iv) precipitating the 14-hydroxymorphinone salt of formula Vfrom the solution or suspension (e.g., by adjusting the temperature ofthe solution and/or adding a suitable antisolvent to the solution, asdescribed in more detail below). In certain embodiments, precipitationis achieved by adding a suitable antisolvent. In certain embodiments,precipitation is achieved by lowering the temperature below the reactiontemperature of the oxidation reaction.

In certain embodiments, the amount of compounds of formula III in thereaction product containing the compound of formula V is less than about2500 ppm, less than about 2000 ppm, less than about 1500 ppm, less thanabout 1000 ppm, less than about 500 ppm, less than about 100 ppm, lessthan about 50 ppm, less than about 10 ppm, less than about 5 ppm, orless than about 1 ppm of the compound of formula V. In certainembodiments, the amount of compounds of formula III in the reactionproduct containing the compound of formula V is the amount described inSection III. In certain embodiments, the reaction product is free fromcompounds of formula III.

In certain embodiments, oripavine is oxidized to 14-hydroxymorphinone,wherein the reaction mixture comprises more than one acid (e.g., twoacids), and comprises less than about 14 molar equivalents of total acidper molar equivalent of oripavine (e.g., from about 0.5 to about 11,from about 1 to about 10.5, from about 1.5 to about 5, or from about 3to about 5 molar equivalents of acid per molar equivalent of oripavine).

In certain embodiments, oripavine is oxidized to 14-hydroxymorphinone,wherein the reaction mixture comprises more than one acid (e.g., twoacids), and comprises less than about 8 molar equivalents of total acidper molar equivalent of oripavine (e.g., from about 0.5 to about 7, fromabout 1 to about 5, from about 1.2 to about 4.5, from about 2.5 to about4.5, or from about 3 to about 4 molar equivalents of total acid permolar equivalent of oripavine).

In certain embodiments of the process, oripavine is oxidized to14-hydroxymorphinone in a solution or suspension containing a mixture offormic acid and sulfuric acid, the mixture comprising not more thanabout 14 molar equivalents of total acid per one molar equivalent oforipavine (e.g., from about 0.5 to about 11, from about 1 to about 10.5,from about 1.5 to about 5, or from about 3 to about 5 molar equivalentsof acid per one molar equivalent of oripavine).

There are also alternative ways to perform step (b) than by adding H⁺_(n)X^(n−) to the reaction mixture. In step (b) of the process, the H⁺_(n)X^(n−) can be generated by adding a salt containing X^(n−). Saidsalt may have the formula

M ^(m+)(H ⁺)_((n-m)) X ^(n−), or M ^(m+) _(((n-1)/m))(H ⁺)₁ X ^(n−),wherein

M^(m+) is a monovalent or polyvalent metal cation;m and n are independently from each other an integer selected from 1, 2,and 3, provided thatm is ≦n; and1 is an integer selected from 0, 1, and 2, provided that 1<n.

The metal cation may be an alkali metal cation, an alkaline earth metalcation or a Group III cation. Exemplary cations are Na⁺, K⁺, Ca²⁺.Exemplary salts are NaHSO₄, KHSO₄, Na₂SO₄, K₂SO₄, NaH₂PO₄, Na₂HPO₄,Na₃PO₄, KH₂PO₄, K₂HPO₄, K₃PO₄.

As a further alternative to adding an acid H⁺ _(n)X^(n−) in step (b),step (b) may be performed by adding a Lewis acid to the reaction mixtureinstead of the acid H⁺ _(n)X^(n−). Such Lewis acid may be aluminumchloride (AlCl₃), aluminum bromide (AlBr₃), boron trifluoride (BF₃),boron trifluoride diethyl etherate (BF₃.Et₂O), iron (III) chloride(FeCl₃) or the like.

The oxidation reaction may be prepared in any suitable reaction vessel.In certain embodiments, the reaction vessel is a flow reactor. Incertain other embodiments, the reaction vessel is not a flow reactor. Incertain embodiments, the reaction vessel is a continuous flow reactor.In certain other embodiments, the reaction vessel is not a continuousflow reactor.

Precipitation and/or Isolation of the Compound of Formula V

The compound of formula V according to present invention or the solvatethereof may be provided as a solid, or in solution or suspension as aresult of the process encompassing steps (a) and (b). In certainpreferred embodiments, the process is performed under conditions whereinthe compound of formula V or a solvate thereof is insoluble in thereaction mixture. In these embodiments, the process may comprise anadditional step (c) of precipitating the compound of formula V or thesolvate thereof from the reaction mixture.

As already pointed out in the Definitions section, “precipitating”encompasses “crystallizing” unless stated otherwise.

The precipitation of the compound of formula V or the solvate thereof isconsidered to be surprising because of the acidic pH of the reactionmixture.

The precipitation may start as soon as H⁺ _(n)X^(n−) is present in thereaction mixture (e.g., after addition of an acid H⁺ _(n)X^(n−)), or itmay start at a later point in time. In other words, it may take placeduring and/or after the oxidation reaction.

The precipitation of the compound of formula V or the solvate thereofmay be caused by the presence of the acid H⁺ _(n)X^(n−) in the reactionmixture. It may be enhanced by adding an additional amount of the acidH⁺ _(n)X^(n−) or the salt containing X^(n−) to the reaction mixtureduring step (b).

In certain embodiments, the precipitation of the compound of formula Vor the solvate thereof may require the cooling of the reaction mixtureand/or the addition of an antisolvent.

In certain embodiments wherein the compound of formula V or a solvatethereof precipitates from the reaction mixture, the acid H⁺ _(n)X^(n−)is H₂SO₄ or its monosalt, methanesulfonic acid, tosylic acid,trifluoroacetic acid, H₃PO₄ or one of its mono- or disalts, oxalic acid,perchloric acid, or any mixtures thereof. In certain embodiments, it maybe H₂SO₄, methanesulfonic acid, tosylic acid, trifluoroacetic acid, or amixture thereof. In certain embodiments, it is H₂SO₄, methanesulfonicacid, or trifluoroacetic acid or a mixture thereof. In certainembodiments, it is trifluoroacetic acid. In certain embodiments, it isH₂SO₄. In certain embodiments, it is methanesulfonic acid.

The compound of formula V or the solvate thereof, once precipitated, mayeither be isolated (i.e. separated from the reaction mixture), or it maybe converted without preceding isolation to further compounds, e.g., toa compound of formula IV or a salt or solvate thereof

Once precipitated and isolated, the precipitate containing the compoundof formula V may, optionally, be subject to one or more further steps toreduce the amount of any residual compound of formula III therein (e.g.,(re)crystallization or heat treatment) which are described in thesubsequent section.

Precipitation of the compound of formula V may be influenced by themolar ratio of the anion X^(n−) to the compound of formula I (seeabove), by the amount of total acid present during the oxidationreaction (as compared to molar equivalents of the compound of formulaI), by the temperature before, during or after the oxidation reaction,by the kind and amount of solvent (e.g., water) present in the reactionmixture, by the presence of an antisolvent added to the reactionmixture, by the rate at which the reactants are added during the processto the reaction mixture, or by a combination of any of the foregoing.

In certain embodiments, the precipitation of the compound of formula Vor a solvate thereof is initiated and/or enhanced by one or more of thefollowing:

(i) adjusting (e.g., lowering) the temperature of the reaction mixtureto the precipitation temperature;(ii) addition of an antisolvent;(iii) addition of a seed crystal;(iv) lowering the pH;(v) changing the ionic strength of the reaction mixture (e.g., byaddition of a salt);(vi) concentrating the reaction mixture;(vii) reducing or stopping agitation of the reaction mixture;or any other conventional method for initiating or enhancingprecipitation or crystallization.

When the temperature is adjusted to the precipitation temperature, thismeans that the precipitation of the compound of formula V or the solvatethereof is initiated and/or enhanced by adjusting the temperature of thereaction mixture to or beyond a temperature at which said compoundprecipitates (“precipitation temperature”). The temperature is eitheradjusted by performing the reaction at the precipitation temperature, orby lowering the temperature of the reaction mixture during the reactionor after completion of the reaction.

In certain embodiments, the reaction mixture is adjusted to atemperature of <40° C. to initiate precipitation, i.e. the precipitationtemperature is <40° C. In certain embodiments, the precipitation isinitiated at a precipitation temperature of about −20° C., about −15°C., about −10° C., about −5° C., about 0° C., about 5° C., about 10° C.,about 15° C., about 17° C., about 19° C., about 21° C., about 23° C.,about 25° C., about 27° C., about 29° C., about 31° C., about 33° C.,about 35° C., about 37° C., or about 40° C.

In certain embodiments, the precipitation temperature is in a range offrom about −20° C. to about 40° C., preferably from about 0° C. to about40° C., more preferably from about 5° C. to about 35° C., morepreferably from about 5° C. to about 30° C., even more preferably fromabout 5° C. to about 20° C.

In certain embodiments, the precipitation temperature is in a range offrom about 5° C. to about 22° C., preferably from 5° C. to about 18° C.,more preferably from about 8° C. to about 15° C.

In certain embodiments, the precipitation temperature is in a range offrom about 5° C. to about 18° C.; or from about 8° C. to about 15° C.

In certain embodiments, an antisolvent is used in addition to adjustingthe temperature to the precipitation temperature. In certainembodiments, e.g., when the compound of formula V is14-hydroxymorphinone sulfate, precipitation will also occur withoutadding an antisolvent.

If an antisolvent is used for initiating precipitation, theprecipitation temperature may be in a range of from about −20° C. toabout 40° C., from about 0° C. to about 40° C., from about 5° C. toabout 35° C., from about 5° C. to about 22° C., from about 5° C. toabout 18° C.; or from about 8° C. to about 15° C.

In certain embodiments, the reaction mixture is cooled at a controlledrate during precipitation. In certain embodiments, the cooling rate isabout 1° C., about 2° C., about 3° C., about 4° C., or about 5° C. perhour.

An important factor influencing the precipitation of a compound offormula V or a solvate thereof in a process according to presentinvention may be the temperature of the reaction mixture. A furtherfactor influencing the precipitation appears to be the total amount ofacid in the reaction mixture. Another factor influencing theprecipitation appears to be the molarity of the reaction mixture. Theaddition of an antisolvent also appears to be a factor that caninfluence precipitation of a compound of formula V or a solvate thereof.It is presently believed that the precipitation temperature will risewhen the total amount of acid is lowered.

Hence, in a process wherein the compound of formula V or the solvatethereof is precipitated and wherein the total amount of acid present inthe reaction mixture is from about 0.6 to about 14.0 molar equivalentsof total acid per molar equivalent of, the compound of formula I, theprecipitation temperature may be ≦40° C. (i.e. 40° C. or less). In aprocess wherein the total amount of acid present in the reaction mixtureis from about 1 to about 8 molar equivalents, preferably from about 1 toabout 5 molar equivalents of total acid per molar equivalent of thecompound of formula I, the precipitation temperature may be in a rangeof from about 0° C. to about 40° C., preferably from about 0° C. toabout 35° C. In a process wherein the total amount of acid present inthe reaction mixture is from about 1 to about 4 molar equivalents,preferably from about 1 to about 3 molar equivalents of total acid permolar equivalent of the compound of formula I, the precipitationtemperature may be in a range of from about 5° C. to about 22° C.;preferably from about 8° C. to about 20° C., more preferably from about8° C. to about 15° C. Further examples of such correlations can be foundin the Examples section.

In certain embodiments, an antisolvent is added to precipitate acompound of formula V or a solvate thereof. When an antisolvent is addedto the reaction mixture, it is added either during or after step (b) andin an effective amount to initiate and/or enhance precipitation. Incertain embodiments, addition of a suitable antisolvent increases theyield of the reaction. Addition of a suitable antisolvent may alsoenhance retention of compound of formula III in the supernatant. Asuitable antisolvent may comprise or consist of tert-butyl methyl ether,diethyl ether, hexane(s), tert-amyl alcohol, methanol, ethanol,isopropanol, 2-butanol, heptanes, xylenes, toluene, acetone, 2-butanone,ethyl acetate, tetrahydrofuran, 1,2-dichloroethane, chloroform,dichloromethane, 1-methoxy-2-propanol, 2-ethoxyethanol, n-propanol,1-butanol, tert-butanol, isobutanol, isopropyl acetate, 1,4-dioxane,2-methyl-tetrahydrofuran, methyl formate, methyl acetate, or a mixtureof two or more of any of the foregoing. 14-Hydroxymorphinone sulfate hasvery low/no solubility in these solvents at room temperature. The listedalcohols and ethers are the preferred antisolvents. In some embodiments,said antisolvent is an alcohol, e.g., methanol, isopropanol or2-butanol. In some embodiments, said antisolvent is an ether, e.g.,tert-butyl methyl ether and/or tetrahydrofuran. In some preferredembodiments, said antisolvent is isopropanol or 2-butanol. In someembodiments, said antisolvent is a mixture of an alcohol (e.g.,methanol) and an ether (e.g., tert-butyl methyl ether and/ortetrahydrofuran), for example a mixture of methanol and tert-butylmethyl ether, or a mixture of methanol and tetrahydrofuran, or a mixtureof tert-butyl methyl ether and tetrahydrofuran, or a mixture ofmethanol, tert-butyl methyl ether, and tetrahydrofuran. When two or moreantisolvents are used (e.g., in a mixture), they can be added as amixture or separately.

When an antisolvent is added, it is preferably added in an amount offrom about 1 to about 5 ml antisolvent per 1 g compound of formula I,more preferably in an amount of from about 2 to about 4 ml antisolventper 1 g compound of formula I. For example, in a preferred embodiment,from about 2 to about 4 ml 2-butanol (e.g., 2.6 ml) per 1 g of oripavineare added. Within these ranges, the yield is especially increased and/orthe retention of compound of formula III in the supernatant isespecially enhanced.

In certain embodiments, an antisolvent is added to precipitate acompound of formula V or a solvate thereof wherein R¹ in the formula IImoiety is —H, e.g., 14-hydroxymorphinone sulfate or a solvate thereof.

When a seed crystal is added, said seed crystal is a crystal of thecompound of formula V or a solvate thereof. This seed crystal may act ascrystallization nucleus if the solution of the compound of formula Vresulting from step (b) is metastable. It may be made metastable byconcentrating the reaction mixture.

In certain embodiments, the precipitate may be isolated from thereaction mixture (isolation step (d)).

In said isolation step (d), the precipitate may be separated from thesupernatant in any conventional manner, e.g., by filtration,centrifugation, decanting, or any other conventional method forseparating a solid phase from a liquid phase. In certain embodiments,the ratio of compounds of formula III (e.g., of 8-hydroxyoxymorphone)(either in its free base form or bound in a salt or solvate) to that offormula II (which may be bound in the compound of formula V) in theprecipitate is less than the ratio of compounds of formula III (e.g., of8-hydroxyoxymorphone) to that of formula II in the supernatant.

In cases where the compound of formula V or a solvate thereof is notprecipitated, it may be isolated by concentrating the reaction mixture,e.g., by drying, vacuum distillation, spray drying or lyophilization.

Further Processing of the Compound of Formula V or the Solvate Thereof

In certain embodiments, the precipitate containing the compound offormula V or the solvate thereof can be further processed.

In certain embodiments, the isolated precipitate containing the compoundof formula V or the solvate thereof is treated with a substance thatconverts a portion or all or substantially all of the compound offormula III contained in said precipitate into a compound of formula II,a salt of a compound of formula H (e.g., into the compound of formulaV), or a compound which will not be converted into the compound offormula II during further processing of the composition.

In certain embodiments, the isolated precipitate containing the compoundof formula V or the solvate thereof is hydrogenated. Generally, thehydrogenation is conducted under conditions which are less severe thanthe hydrogenation conditions described below for the preparation of acompound of formula IV or a salt or solvate thereof. For example, lessacid may be required for the hydrogenation of the compound of formula Vor the solvate thereof.

In certain embodiments, the isolated precipitate containing the compoundof formula V or the solvate thereof is heated to further reduce theamount of a compound of formula III or salt or solvate thereof in thecomposition.

In certain embodiments, the isolated precipitate containing the compoundof formula V or solvate thereof may be washed with and/or(re)crystallized in an organic solvent or aqueous solvent in which acompound of formula III or a salt or solvate thereof is more solublethan the compound of formula V or solvate thereof and/or thecorresponding compound of formula II. The washing and/or(re)crystallization may further reduce the amount of a compound offormula III in the isolated precipitate containing the compound offormula V or solvate thereof. The washing and/or the (re)crystallizationmay be performed more than once, or they may also be combinedsequentially.

In certain embodiments, the isolated precipitate containing the compoundof formula V or solvate thereof is washed with and/or is(re)crystallized in a solvent containing or consisting of an ether, aketone, an ester, an alcohol, water, an (optionally halogenated) alkane,an (optionally halogenated) aromatic solvent or any mixtures thereof.The solvent may contain or consist of one or more of the followingsolvents: methanol, ethanol, isopropanol, 1-butanol, 2-butanol,isobutanol, tert-butanol, acetone, tetrahydrofuran, ethyl acetate,heptane, tert-butyl methyl ether, 1,2-dichloroethane, toluene,2-butanone (MEK), tert-amyl alcohol, chloroform, xylene, and water.

In certain embodiments, the isolated precipitate containing the compoundof formula V or solvate thereof is washed and/or (re)crystallized in asolvent consisting of an ether, an alcohol, water, chloroform, or anymixture thereof. In certain embodiments, said solvent may be methanol,ethanol, n-propanol, isopropanol, 1-butanol, 2-butanol, isobutanol,tert-butanol, acetone, tetrahydrofuran, chloroform, or a mixture ofwater with any of the foregoing.

In certain embodiments, the isolated precipitate containing the compoundof formula V or solvate thereof is washed and/or (re)crystallized with asolvent which is tert-butyl methyl ether, tetrahydrofuran, methanol,ethanol, acetone, isopropanol, 2-butanol, or a mixture ofmethanol:water, THF:water, acetone:water, isopropanol:water,2-butanol:water, or ethanol:water. In certain embodiments, the isolatedprecipitate containing the compound of formula V or solvate thereof iswashed and/or (re)crystallized with a solvent which is tert-butyl methylether, tetrahydrofuran, methanol, a 2-butanol:water mixture, or amethanol:water mixture.

In certain embodiments, preferably wherein the compound of formula V is14-hydroxymorphinone sulfate and the compound of formula III is8-hydroxyoxymorphone, the isolated precipitate containing the compoundof formula V or solvate thereof is washed with and/or (re)crystallizedin a 90:10 methanol:water mixture; 80:20 methanol:water mixture, 70:30methanol:water or 60:40 methanol:water mixture. In certain embodiments,the isolated precipitate containing the compound of formula V or solvatethereof is washed with and/or (re)crystallized in a 80:20 or 70:30methanol:water mixture. 8-Hydroxyoxymorphone (and its correspondingprotonated species) is more soluble in these mixtures than14-hydroxymorphinone sulfate and therefore it is assumed that a compoundof formula III may be removed from the isolated compound of formula V orsolvate thereof by the washing and/or (re)crystallization.

In certain embodiments, preferably wherein the compound of formula V is14-hydroxymorphinone sulfate and the compound of formula III is8-hydroxyoxymorphone, the isolated precipitate containing the compoundof formula V or solvate thereof is washed with and/or (re)crystallizedin a 90:10 ethanol:water mixture, 80:20 ethanol:water mixture or 70:30ethanol:water mixture. In certain embodiments, the isolated precipitatecontaining the compound of formula V or solvate thereof is washed withand/or (re)crystallized in 90:10 ethanol/water mixture.8-Hydroxyoxymorphone (and its corresponding protonated species) is moresoluble in these mixtures than 14-hydroxymorphinone sulfate andtherefore it is assumed that a compound of formula III may be removedfrom the isolated compound of formula V or solvate thereof by thewashing and/or (re)crystallization.

In certain embodiments, preferably wherein the compound of formula V is14-hydroxymorphinone sulfate and the compound of formula III is8-hydroxyoxymorphone, the isolated precipitate containing the compoundof formula V or solvate thereof is washed with and/or (re)crystallizedin tetrahydrofuran or in 90:10 tetrahydrofuran:water mixture.8-Hydroxyoxymorphone (and its corresponding protonated species) is moresoluble in these mixtures than 14-hydroxymorphinone sulfate andtherefore it is assumed that a compound of formula III may be removedfrom the isolated compound of formula V or solvate thereof by thewashing and/or (re)crystallization.

In certain embodiments, preferably wherein the compound of formula V is14-hydroxymorphinone sulfate and the compound of formula III is8-hydroxyoxymorphone, the isolated precipitate containing the compoundof formula V or solvate thereof is washed with and/or (re)crystallizedin a 90:10 isopropanol:water mixture, 80:20 isopropanol:water mixture or70:30 isopropanol:water mixture. In certain embodiments, the isolatedprecipitate containing the compound of formula V or solvate thereof iswashed with and/or (re)crystallized in a 90:10 isopropanol:watermixture. 8-Hydroxyoxymorphone (and its corresponding protonated species)is more soluble in these mixtures than 14-hydroxymorphinone sulfate andtherefore it is assumed that a compound of formula III may be removedfrom the isolated compound of formula V or solvate thereof by thewashing and/or (re)crystallization.

In certain embodiments, preferably wherein the compound of formula V is14-hydroxymorphinone sulfate and the compound of formula III is8-hydroxyoxymorphone, the isolated precipitate containing the compoundof formula V or solvate thereof is washed with and/or (re)crystallizedin a 90:10 2-butanol:water mixture, 80:20 2-butanol:water mixture, 70:302-butanol:water mixture, 60:40 2-butanol:water mixture, or 20:102-butanol:water mixture. In certain embodiments, the isolatedprecipitate containing the compound of formula V or solvate thereof iswashed with and/or (re)crystallized in a 20:10 2-butanol:water mixture.8-Hydroxyoxymorphone (and its corresponding protonated species) is moresoluble in these mixtures than 14-hydroxymorphinone sulfate andtherefore it is assumed that a compound of formula III may be removedfrom the isolated compound of formula V or solvate thereof by thewashing and/or (re)crystallization.

In certain embodiments, preferably wherein the compound of formula V is14-hydroxymorphinone sulfate and the compound of formula III is8-hydroxyoxymorphone, the isolated precipitate containing the compoundof formula V or solvate thereof is washed with and/or (re)crystallizedin a 70:30 acetone:water mixture or 80:20 acetone:water mixture.8-Hydroxyoxymorphone (and its corresponding protonated species) is moresoluble in these mixtures than 14-hydroxymorphinone sulfate andtherefore it is assumed that a compound of formula III may be removedfrom the isolated compound of formula V or solvate thereof by thewashing and/or (re)crystallization.

The washing of the isolated precipitate containing the compound offormula V or solvate thereof may be performed in any way conventional inthe art, e.g., by forming a slurry of the compound.

The precipitate containing the compound of formula V or solvate thereof,whether isolated or not isolated, may be treated with a suitable acid toeffect conversion of a compound of formula III or salt thereof, ifpresent, to ultimately a compound of formula V. In general, any acidknown to be capable of converting a β-hydroxy-ketone to anα,β-unsaturated ketone, under the conditions of the prior art, may beused. A suitable Lewis acid may be, e.g., aluminum chloride (AlCl₃),aluminum bromide (AlBr₃), boron trifluoride (BF₃), boron trifluoridediethyl etherate (BF₃.Et₂O), iron (III) chloride (FeCl₃) or the like. Asuitable Bronsted acid may be, e.g., the acid H⁺ _(n)X^(n−), ethanedioicacid, acetic acid, para-toluene sulfonic acid, a mineral acid or thelike.

The precipitate containing the compound of formula V or solvate thereof,whether isolated or not, may also be treated with a dehydratingreagent(s), e.g., oxalic acid (H₂C₂O₄) or oxalyl chloride (COCl)₂,phosphorous trichloride (PCl₃), phosphoryl trichloride (POCl₃), thionylchloride (SOCl₂), sulfuryl chloride (SO₂Cl₂), or the like, undersuitable conditions to effect conversion of a compound of formula III orsalt thereof, if present, to ultimately a compound of formula V.

The precipitate containing the compound of formula V or solvate thereofmay also be treated with an oxidizing agent, e.g., potassiumpermanganate (KMnO₄), chromium (VI) oxide (CrO₃), DMF-Cl, (CH₃)₂SCI, orthe like, under suitable conditions to effect oxidation of any compoundof formula III or salt thereof, if present.

In certain embodiments, the amount of any compound of formula III orsalt thereof in a product containing the compound of formula V orsolvate thereof prepared by a process comprising the step ofprecipitating and isolating the compound of formula V or solvate thereofas described herein is less than the corresponding amount of thecompound of formula III or salt thereof in a product containing thecorresponding compound of formula II prepared by a processes which doesnot include the formation and isolation of a compound of formula V orsolvate thereof.

In certain embodiments, the ratio of compound of formula III to compoundof formula V in the supernatant after the precipitation of the compoundof formula V or solvate thereof is higher than the ratio of compound offormula III to compound of formula V in the precipitate.

Preferred Process Conditions

A preferred set of reaction conditions for the oxidation process and thesubsequent isolation of the compound of formula V is described in thefollowing. Therein, the compound of formula V is preferably14-hydroxymorphinone sulfate, and the compound of formula I ispreferably oripavine.

The process is performed by: (i) forming a solution or a suspensioncomprising the compound of formula I, from about 1.5 to about 2.0 mlwater per g compound of formula I, and from about 2.5 to about 4.5 molarequivalents of formic acid per molar equivalent of compound of formulaI, (ii) adding from about 0.5 to about 0.6 molar equivalents of sulfuricacid per molar equivalent of the compound of formula I to the solutionor the suspension, (iii) adding from about 1.0 to about 1.4 molarequivalents, preferably from about 1.2 to about 1.4 molar equivalents,more preferably from about 1.2 to about 1.3 molar equivalents ofhydrogen peroxide to the solution or the suspension from (ii), thenincubating the mixture at a temperature of from about 30° C. to about38° C., preferably of from about 32° C. to about 36° C., more preferablyof about 35° C., until the conversion is complete, and (iv)precipitating the compound of formula V from the resulting solution orsuspension. Step (iv) may be performed by adding a suitable antisolventto the solution, as described in detail above. A preferred antisolventmay be an alcohol, in particular isopropanol or 2-butanol. Preferably,from about 2 to about 4 ml antisolvent per 1 g compound of formula I areadded.

When the compound of formula V is 14-hydroxymorphinone sulfate, and thecompound of formula I is preferably oripavine, the process is preferablyperformed by: (i) forming a solution or a suspension by mixing theoripavine, from about 1.5 to about 2.0 ml water per g oripavine, andfrom about 2.5 to about 4.5 molar equivalents of formic acid per molarequivalent of oripavine, (ii) adding from about 0.5 to about 0.6 molarequivalents of sulfuric acid per molar equivalent of oripavine to thesolution or the suspension, (iii) adding from about 1.0 to about 1.4molar equivalents, preferably from about 1.2 to about 1.4 molarequivalents, more preferably from about 1.2 to about 1.3 molarequivalents of hydrogen peroxide to the solution or the suspension from(ii), then incubating the mixture at a temperature of from about 30° C.to about 38° C., preferably of from about 32° C. to about 36° C., morepreferably of about 35° C., until the conversion is complete, and (iv)precipitating the 14-hydroxymorphinone sulfate from the resultingsolution or suspension. Step (iv) may be performed by adding a suitableantisolvent to the solution, as described in detail above. A preferredantisolvent may be an alcohol, in particular isopropanol or 2-butanol.Preferably, from about 2 to about 4 ml antisolvent per 1 g oripavine areadded.

III. Levels of the Compound of Formula III in the Product ContainingCompound of Formula V Resulting from the Process According to Section II

Thus, the present invention provides a process for preparing a compoundof formula V or a solvate thereof as represented in Scheme 15:

The product of the process is the compound of formula V or a solvatethereof in its dissolved (unprecipitated) or solid (precipitated (e.g.,crystallized)), and optionally further processed form.

The product of the process may contain a compound of formula III or saltthereof as a by-product of the oxidation reaction, as illustrated in thefollowing reaction Scheme 16:

Said compound of formula III may be present in the product in the formof its free base, or in the form of its salt or solvate. Under the acidconditions of the oxidation reaction according to the present invention,it is typically present in its protonated form and will therefore form asalt or a solvate thereof.

Said compound of formula III may be present in the reaction mixture atthe end of the process in dissolved or precipitated form. In embodimentswhere the compound of formula V is precipitated, said compound offormula III may be present in the precipitate, in the mother liquor, orin both.

Hence, the present invention also provides a process for preparing acomposition comprising a compound of formula V or a solvate thereof, anda compound of formula III or a salt or solvate thereof as a by-product.The embodiments for performing said process are described in Section II.

Whenever compound of formula III is comprised in the process product(which is a composition as defined in the preceding paragraph), it ispresent in a certain amount which shall be specified in the following.

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof which is present in the process product is lessthan the amount of the compound of formula III or salt or solvatethereof which is present in a product of the same process performed inthe absence of the acid H⁺ _(n)X^(n−).

In certain embodiments, the process product containing the compound offormula V or a solvate thereof contains an amount of formula III or asalt or solvate thereof which is less than the amount of the compound offormula III or salt or solvate thereof which would be present in aprocess product containing the corresponding compound of formula II orsalt or solvate thereof prepared by the process in the absence of theacid H⁺ _(n)X^(n−).

In certain embodiments, the compound of formula V or solvate thereof isprecipitated during the process and the precipitate contains lesscompound of formula III or salt or solvate thereof in relation tocompound of formula V or solvate thereof than the mother liquor.

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the process product containing the compoundof formula V or solvate thereof is less than about 2500 ppm, less thanabout 2250 ppm, less than about 2000 ppm, less than about 1750 ppm, lessthan about 1500 ppm, or less than about 1250 ppm of the compound offormula V (HPLC peak area ratio).

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the process product containing the compoundof formula V or solvate thereof is less than about 1000 ppm, less thanabout 750 ppm, less than about 500 ppm, or less than about 400 ppm ofthe compound of formula V or solvate thereof (HPLC peak area ratio).

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the process product containing the compoundof formula V or solvate thereof is less than about 300 ppm, less thanabout 275 ppm, less than about 250 ppm, less than about 225 ppm, lessthan about 200 ppm, less than about 175 ppm, less than about 150 ppm, orless than about 125 ppm of the compound of formula V or solvate thereof(HPLC peak area ratio).

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the process product containing the compoundof formula V or solvate thereof is less than about 100 ppm, less thanabout 90 ppm, less than about 80 ppm, less than about 70 ppm, less thanabout 60 ppm, less than about 50 ppm, less than about 40 ppm, less thanabout 30 ppm, or less than about 20 ppm of the compound of formula V orsolvate thereof (HPLC peak area ratio).

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the process product containing the compoundof formula V or solvate thereof is less than about 10 ppm, less thanabout 8 ppm, less than about 6 ppm, less than about 4 ppm, or less thanabout 2 ppm of the compound of formula V or solvate thereof (HPLC peakarea ratio).

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the process product containing the compoundof formula V or solvate thereof is less than about 1 ppm, less thanabout 0.8 ppm, less than about 0.6 ppm, less than about 0.4 ppm, lessthan about 0.3 ppm, less than about 0.2 ppm, or less than about 0.1 ppmof the compound of formula V or solvate thereof (e.g., the amount of8-hydroxyoxymorphone is from about 0.05 ppm to about 0.7 ppm of the14-hydroxymorphinone sulfate) (HPLC peak area ratio).

The amount of the compound of formula III or salt or solvate thereof inthe process product containing the compound of formula V or solvatethereof may have a lower limit of about 0.01 ppm of the compound offormula V or solvate thereof (HPLC peak area ratio). The lower limit mayalso be about 0.05 ppm, about 0.1 ppm, about 0.3 ppm, about 0.5 ppm,about 0.7 ppm, about 1 ppm, about 1.5 ppm, about 2 ppm, or about 3 ppm.For example, the amount of the compound of formula III or salt orsolvate thereof in the compound of formula V or salt or solvate thereofmay range from about 0.05 ppm to 1 ppm in a certain embodiment, and fromabout 1 ppm to about 10 ppm in a certain other embodiment.

The process product containing the compound of formula V or solvatethereof in certain embodiments comprises from about 0.01 ppm to about2500 ppm, from about 0.05 to about 2250 ppm, from about 0.1 ppm to about2000 ppm, from about 0.3 to about 1750 ppm, from about 0.5 ppm to about1500 ppm, or from about 1 ppm to about 1250 ppm compound of formula IIIor a salt or solvate thereof in relation to the compound of formula V(HPLC peak area ratio).

The process product containing the compound of formula V or solvatethereof in certain embodiments comprises from about 0.05 ppm to about1000 ppm, from about 0.1 ppm to about 800 ppm, from about 0.1 ppm toabout 700 ppm, from about 0.2 ppm to about 600 ppm, from about 0.3 ppmto about 500 ppm, or from about 0.5 ppm to about 400 ppm compound offormula III or salt or solvate thereof in relation to the compound offormula V.

The process product containing the compound of formula V or solvatethereof in certain embodiments comprises from about 0.05 ppm to about350 ppm, from about 0.1 ppm to about 300 ppm, from about 0.2 ppm toabout 275 ppm, from about 0.3 ppm to about 250 ppm, from about 0.4 ppmto about 225 ppm, or from about 0.5 ppm to about 200 ppm compound offormula III or salt or solvate thereof in relation to compound V.

In certain embodiments, the process product containing the compound offormula V or solvate thereof does not contain compound of formula III.

In certain embodiments, the process product containing the compound offormula V comprises the 8α stereoisomer, the 8β stereoisomer, or amixture of these two stereoisomers of a compound of formula III. In oneembodiment, the compound of formula V is a (14-hydroxymorphinone)salt(e.g., 14-hydroxymorphinone sulfate), and the compound of formula IIImay be 8-hydroxyoxymorphone having 8α and/or 8β stereoconfiguration.

As already indicated in Section II, in certain embodiments of theoxidation process according to the present invention said result may beachieved because the formation of the compound of formula V or a solvatethereof has the effect that less 8-hydroxy compound of formula III isformed during the oxidation reaction in comparison to an oxidationreaction where no compound of formula V or solvate thereof is formed. Inother words, the formation of the compound of formula V allows for animprovement of the by-product profile of the reaction product. Oneexample for such embodiment may be the formation of a compound offormula V wherein n is 2 and preferably wherein X^(n−) is sulfate.Another example for such embodiment may be the formation of a compoundof formula V wherein n is 1 and preferably wherein X^(n−) istrifluoroacetate.

In certain other embodiments of the oxidation process according to thepresent invention said result may be achieved because the formation offormula V or a solvate thereof has the effect that compounds of formulaIII can be separated from the compound of formula V or the solvatethereof, e.g., by precipitation of the compound of formula V or thesolvate thereof from the reaction mixture. One example for such anembodiment may be the formation of a compound of formula V whereinX^(n−) is sulfate. One example for such an embodiment may be the use ofone of the antisolvents described in Section II.

In certain embodiments a combination of these effects takes place. Thatis, said result is achieved because both less compounds of formula IIIare formed during the oxidation and because said compounds of formulaIII can be separated from the compound of formula V or solvate thereof.One example for such an embodiment may be the formation of a compound offormula V wherein X^(n−) is sulfate, preferably in combination with oneof the antisolvents described in Section II.

IV. Compound Having the Formula V

The present invention further provides a compound having the formula Vor a solvate thereof

wherein R¹, R², X^(n−) and n are defined as above, in particular insection I. Present invention provides said compound of formula V orsolvate thereof as a solid, in solution or as a suspension.

The compound of formula V or solvate thereof comprises one or moreprotonated molecules of formula II and at least one anion X^(n−). Theanion may be an organic or inorganic anion. The anion may be mono- orpolyvalent (e.g., divalent or trivalent). In its solid form, thecomponents of the compound of formula V are present in stoichiometricamounts. However, other molecular ratios may also be present either inmicro- or macrostructures of the salt, depending e.g., on the type ofthe anion and valency thereof, the solvent (which might also form partof the salt) and the ambient pH.

In certain embodiments, said compound of formula V or solvate thereof isprovided in its isolated, solid form, which in certain embodiments isits crystalline form.

Said compound of formula V or solvate thereof may be obtainable orobtained by the process described in section II. In these embodiments,the process product may have the properties as described in section III.

Said compound of formula V or solvate thereof is an embodiment of thepresent invention, on its own right, and in its function as a startingmaterial or as intermediate for the synthesis of compounds of formula IVor (pharmaceutically acceptable) salts or solvates thereof. Acomposition comprising said product of formula V or solvate thereof, asdescribed in more detail in Section IV-A, is also an embodiment of thepresent invention on its own right, and in its function as a startingmaterial or as intermediate for the synthesis of compounds of formula IVor (pharmaceutically acceptable) salts or solvates thereof.

In certain embodiments of the compound of formula V or solvate thereof,n is 1 or 2, and is preferably 2.

In certain embodiments, X^(n−) is SO₄ ²⁻ or trifluoroacetate, and ispreferably SO₄ ²⁻.

In certain embodiments, the compound of formula V is provided as itssolvate. Said solvate may be any association product of a compound offormula V with a solvent molecule. The molar ratio of solventmolecule(s) per molecule of formula V may vary. The molar ratio ofsolvent to compound/salt in the solvate may be 1 (e.g., in amonohydrate), more than 1 (e.g., 2, 3, 4, 5 or 6 in a polyhydrate), orless than 1 (e.g., in a hemihydrate). The molar ratio need not be aninteger ratio, it can also be, e.g., 0.5 (as in a hemihydrate) or 2.5.For example, 1 molecule water per molecule of 14-hydroxymorphinonesulfate is bound in 14-hydroxymorphinone sulfate monohydrate. Thesolvate of the compound of formula V is in certain embodiments ahydrate, for example a monohydrate, dihydrate, trihydrate, tetrahydrate,pentahydrate or hexahydrate, or a hydrate wherein the ratio of water permolecule is not necessarily an integer, but within the range of from 0.5to 10.0. In certain embodiments, the solvate of the compound of formulaV is a hydrate wherein the ratio of water per molecule is within therange of from 1 to 8. In certain embodiments, the solvate of thecompound of formula V is a hydrate wherein the ratio of water permolecule is within the range of from 1 to 6, i.e. a mono- tohexahydrate. In certain embodiments, the solvate of the compound offormula V is a monohydrate or a pentahydrate.

In certain embodiments, R¹ is —H and/or R² is —CH₃. In other words, inthese embodiments the compound of formula V may be a14-hydroxymorphinone salt or solvate thereof.

In certain embodiments, R¹ is —H and/or R² is —H. In other words, inthese embodiments the compound of formula V may be a14-hydroxy-normorphinone salt or solvate thereof.

In certain embodiments, the compound of formula V is

or a solvate thereof. The solvate may be a hydrate. The molar ratio ofsolvent to compound/salt in the solvate may be 1 (e.g., in amonohydrate), more than 1 (e.g., 2, 3, 4, 5 or 6 in a polyhydrate), orless than 1 (e.g., in a hemihydrate). The molar ratio need not be aninteger ratio, it can also be, e.g., 0.5 (as in a hemihydrate) or 2.5.For example, 1 molecule water per molecule of 14-hydroxymorphinonesulfate is bound in 14-hydroxymorphinone sulfate monohydrate. Thesolvate is in certain embodiments a hydrate, for example a monohydrate,dihydrate, trihydrate, tetrahydrate, pentahydrate or hexahydrate, or ahydrate wherein the ratio of water per molecule is not necessarily aninteger, but within the range of from 0.5 to 10.0. In certainembodiments, the solvate is a hydrate wherein the ratio of water permolecule is within the range of from 1 to 8. In certain embodiments, thesolvate is a hydrate wherein the ratio of water per molecule is withinthe range of from 1 to 6, i.e. a mono to hexahydrate. In certainembodiments, the solvate is a monohydrate or a pentahydrate.

In certain embodiments, the compound of formula V is not14-hydroxymorphinone triflate, or 14-hydroxymorphinone chloride.

In certain embodiments, in the compound of formula V the anion X^(n−) isnot SO₄ ²⁻ when

R¹ is —H; and

R² is selected from —H, —CH₃, optionally unsaturated —(C₂-C₆)alkyl, and—(C₁-C₄)alkyl substituted with at least one cycloalkyl group.

The compound of formula V or solvate thereof may be used as anintermediate or starting material for preparing another opioid or saltor solvate thereof, and for preparing an API which is an opioid or apharmaceutically acceptable salt or solvate thereof, and/or apharmaceutical composition or dosage form containing such API.

Pharmaceutical compositions and dosage forms produced from said compoundof formula V or solvate thereof, preferably, contain less compound offormula III and/or formula II than pharmaceutical compositions preparedvia a different intermediate, i.e. without the compound of formula V.

Compounds and compositions which may be prepared from the compound offormula V or a solvate thereof will be described in the subsequentsections.

IV-A. Compositions Comprising Compound of Formula V

The present invention further provides a composition comprising acompound of formula V or a solvate thereof.

Said composition may be the product of the process described in SectionII.

Said composition may be solid, or a suspension, or a solution. Incertain embodiments, it is a solid. In certain embodiments, it is theprecipitate containing the compound of formula V as described in SectionIV.

In certain embodiments, the composition comprising the compound offormula V or solvate thereof additionally comprises a compound offormula III:

wherein R¹ and R² are defined as in the compound of formula V,or a salt or solvate thereof.

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the composition is the amount as described inSection III.

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the composition is less than about 2500 ppm,less than about 2250 ppm, less than about 2000 ppm, less than about 1750ppm, less than about 1500 ppm, or less than about 1250 ppm of thecompound of formula V (HPLC peak area ratio).

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the composition is less than about 1000 ppm,less than about 750 ppm, less than about 500 ppm, or less than about 400ppm of the compound of formula V or solvate thereof (HPLC peak arearatio).

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the composition is less than about 300 ppm,less than about 275 ppm, less than about 250 ppm, less than about 225ppm, less than about 200 ppm, less than about 175 ppm, less than about150 ppm, or less than about 125 ppm of the compound of formula V orsolvate thereof (HPLC peak area ratio).

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the composition is less than about 100 ppm,less than about 90 ppm, less than about 80 ppm, less than about 70 ppm,less than about 60 ppm, less than about 50 ppm, less than about 40 ppm,less than about 30 ppm, or less than about 20 ppm of the compound offormula V or solvate thereof (HPLC peak area ratio).

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the composition is less than about 10 ppm,less than about 8 ppm, less than about 6 ppm, less than about 4 ppm, orless than about 2 ppm of the compound of formula V or solvate thereof(HPLC peak area ratio).

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the composition is less than about 1 ppm,less than about 0.8 ppm, less than about 0.6 ppm, less than about 0.4ppm, less than about 0.3 ppm, less than about 0.2 ppm, or less thanabout 0.1 ppm of the compound of formula V or solvate thereof (e.g., theamount of 8-hydroxyoxymorphone is from about 0.05 ppm to about 0.7 ppmof the 14-hydroxymorphinone sulfate) (HPLC peak area ratio).

In certain embodiments, the process product containing the compound offormula V or solvate thereof does not contain compound of formula III.

In certain embodiments, the compound of formula V is14-hydroxymorphinone sulfate, and the amount of 8-hydroxyoxymorphone inthe composition is less than about 300 ppm, less than about 275 ppm,less than about 250 ppm, less than about 225 ppm, less than about 200ppm, less than about 175 ppm, less than about 150 ppm, less than about125 ppm, less than about 100 ppm, less than about 80 ppm, less thanabout 60 ppm, less than about 40 ppm, less than about 30 ppm, or lessthan about 20 ppm of the 14-hydroxymorphinone sulfate (HPLC peak arearatio). In certain embodiments, it is less than about 10 ppm, less thanabout 8 ppm, less than about 6 ppm, less than about 4 ppm, less thanabout 2 ppm, less than about 1 ppm, less than about 0.8 ppm, less thanabout 0.6 ppm, less than about 0.4 ppm, less than about 0.3 ppm, lessthan about 0.2 ppm, or less than about 0.1 ppm of the14-hydroxymorphinone sulfate (HPLC peak area ratio). In certainembodiments, the 14-hydroxymorphinone sulfate does not contain8-hydroxyoxymorphone.

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the composition has a lower limit of about0.05 ppm of the compound of formula V or solvate thereof (HPLC peak arearatio). In certain embodiments, the lower limit is about 0.1 ppm, about0.3 ppm, about 0.5 ppm, about 0.7 ppm, about 1 ppm, about 1.5 ppm, about2 ppm, or about 3 ppm. For example, the amount of the compound offormula III or salt or solvate thereof in the composition may range fromabout 0.05 ppm to 1 ppm in a certain embodiment, and from about 1 ppm toabout 10 ppm in a certain other embodiment.

The composition in certain embodiments comprises from about 0.01 ppm toabout 2500 ppm, from about 0.05 to about 2250 ppm, from about 0.1 ppm toabout 2000 ppm, from about 0.3 to about 1750 ppm, from about 0.5 ppm toabout 1500 ppm, or from about 1 ppm to about 1250 ppm compound offormula III or a salt or solvate thereof in relation to the compound offormula V (HPLC peak area ratio).

The composition in certain embodiments comprises from about 0.05 ppm toabout 1000 ppm, from about 0.1 ppm to about 800 ppm, from about 0.1 ppmto about 700 ppm, from about 0.2 ppm to about 600 ppm, from about 0.3ppm to about 500 ppm, or from about 0.5 ppm to about 400 ppm compound offormula III or salt or solvate thereof in relation to the compound offormula V.

The composition in certain embodiments comprises from about 0.05 ppm toabout 350 ppm, from about 0.1 ppm to about 300 ppm, from about 0.2 ppmto about 275 ppm, from about 0.3 ppm to about 250 ppm, from about 0.4ppm to about 225 ppm, or from about 0.5 ppm to about 200 ppm compound offormula III or salt or solvate thereof in relation to compound V.

The composition comprising the compound of formula V and additionallythe compound of formula III may comprise the compound of formula III as(i) 8α isomer, (ii) 813 isomer or (iii) a combination of 8α and 8βisomer. In said embodiments, the compound of formula II (which iscontained in the compound of formula V) may be 14-hydroxymorphinone, andthe compound of formula III may be 8-hydroxyoxymorphone. In saidembodiments, the compound of formula V may be 14-hydroxymorphinonesulfate and the compound of formula III may be 8-hydroxyoxymorphone.

The composition comprising the compound of formula V or solvate thereofmay be used as an intermediate or starting material for preparinganother opioid or salt or solvate thereof, and for preparing an APIwhich is an opioid or a pharmaceutically acceptable salt or solvatethereof, and/or a pharmaceutical composition or dosage form containingsuch API.

Pharmaceutical compositions and dosage forms produced from saidcomposition comprising the compound of formula V or solvate thereof,preferably, contain less compound of formula III and/or formula H thanpharmaceutical compositions prepared via a different intermediate.

Compounds and compositions which may be prepared from the compositioncomprising the compound of formula V or a solvate thereof will bedescribed in the subsequent sections.

V. Processes for Preparation of Compounds of Formula IV or(Pharmaceutically Acceptable) Salts or Solvates Thereof

Present invention further provides a process for preparing a compound offormula IV or an (optionally pharmaceutically acceptable) salt orsolvate thereof from a compound having formula V or a solvate thereof asrepresented in the following Scheme 17:

the process comprising the steps of(e) providing a solution or suspension comprising the compound offormula V or a solvate thereof as defined above; and(f) reducing the compound of formula V to the compound of formula IV ora salt or solvate thereof,wherein R¹, R², X^(n−) and n are defined as above.

In certain embodiments, the solution or suspension comprising thecompound of formula V or the solvate thereof is provided in step (e) byperforming steps (a) to (b) of the process described in Section II,steps (a) to (c) of the process described in section II, or steps (a) to(d) of the process described in Section II. When steps (a) to (d) areperformed, the compound of formula V or solvate thereof isolated in step(d) is dissolved or suspended to provide the solution or suspension ofsaid compound in step (e).

In certain embodiments, the solution or suspension comprising thecompound of formula V or the solvate thereof is the compositiondescribed in Section IV-A.

In certain embodiments, the reduction reaction in step (f) is performedby hydrogenation. Said hydrogenation may be hydrogenation with H₂ ortransfer hydrogenation. Typically, the hydrogenation is performed in thepresence of a hydrogenation catalyst.

An exemplary hydrogenation reaction is depicted in Scheme 18:

Scheme 18 takes into account that 8-hydroxyoxymorphone (or, in general,an 8-hydroxy compound of formula III) or a salt thereof may be presentin the starting material in addition to 14-hydroxymorphinone sulfate (orany other compound of formula V). Said 8-hydroxy compound may carry overduring the reduction reaction. Or, as discussed above, if the reductionis performed under acidic conditions, said 8-hydroxy compound may beconverted partially or completely to the corresponding 14-hydroxycompound of formula II (in Scheme 18: 14-hydroxymorphinone) during thereduction reaction. Thus, compound of formula II (in Scheme 18:14-hydroxymorphinone) and compound of formula III (in Scheme 18:8-hydroxyoxymorphone) may be present in the reaction product whichcontains compound of formula IV (in Scheme 18: oxymorphone) as mainreduction product.

A further exemplary hydrogenation reaction is depicted in Scheme 18A:

Scheme 18A, like Scheme 18, takes into account the presence of8-hydroxyoxymorphone and the consequences of said presence. Deviatingfrom Scheme 18, the reaction in Scheme 18A does not require step (2),i.e. the addition of a base like NH₄OH after the reduction reaction.Thus, the products of the reduction reaction may be present in theirprotonated form or as a salt or solvate thereof. In one embodiment ofthe present invention, the compound of formula IV (represented byoxymorphone in Scheme 18A) is present as a salt or solvate thereof,wherein the salt has the same anion X^(n−) as the anion X^(n−) of thestarting material compound V. Said anion X^(n−) is represented bysulfate in Scheme 18A. In a preferred aspect, the compound of formula IVis present as its sulfate salt or solvate thereof, and it is preferablyprecipitated during or after the reduction reaction and then isolated inits solid form. In another preferred aspect, the compound of formula IVis present as its trifluoroacetate salt or solvate thereof, and it ispreferably precipitated during or after the reduction reaction and thenisolated in its solid form.

Thus, in one embodiment, the compound of formula IV is present as itssalt with anion X^(n−) (e.g., as its sulfate salt) in the reactionmixture during and after the reduction reaction, and this salt or asolvate thereof may be optionally isolated from the reaction mixture,e.g. by precipitation and subsequent isolation of the precipitate. Insaid embodiment, the process may be represented by the followingreaction scheme:

the process comprising the steps of(e) providing a solution or suspension of the compound having formula Vor a solvate thereof; and(f) reducing the compound of formula V to the salt of the compound offormula IV with H⁺ _(n)X^(n−); and optionally(g) isolating the salt of the compound of formula IV with H⁺ _(n)X^(n−),wherein R¹, R², X^(n−) and n are defined as above, and X^(n−) ispreferably SO₄ ²⁻.

The present invention also provides a process wherein a compound offormula II is converted to a salt of the compound of formula IV with H⁺_(n)X^(n−), e.g. to a sulfate salt of formula IV. This conversion isachieved by reduction of the compound of formula II in the presence ofthe acid H⁺ _(n)X^(n−). The acid H⁺ _(n)X^(n−) may be added before orduring the reduction reaction. Optionally, additional acid H⁺ _(n)X^(n−)may be added after the reduction reaction in order to enhanceprecipitation. The resulting salt of the compound of formula IV with H⁺_(n)X^(n−) may be optionally isolated from the reaction mixture, e.g. byprecipitation and subsequent isolation of the precipitate. In saidembodiment, the process may be represented by the following reactionscheme:

the process comprising the steps of(e) providing a solution or suspension of the compound having formula IIor a solvate thereof; and(f) reducing the compound of formula II in the presence of an acid H⁺_(n)X^(n−) to the salt of the compound of formula IV with H⁺ _(n)X^(n−);and optionally(g) isolating the salt of the compound of formula IV with H⁺ _(n)X^(n−),wherein R¹, R², X^(n−) and n are defined as above, and X^(n−) ispreferably SO₄ ²⁻. This reduction is performed using the free base II.Said base may be provided by isolating it as intermediate from acompound of formula V. Moreover, the salt of the compound of formula IVprepared by said process is preferably oxymorphone sulfate or a solvatethereof. I.e., in a preferred aspect of this process,14-hydroxymorphinone base is converted to oxymorphone sulfate (or asolvate thereof). A process for preparing a salt of IV wherein X^(n−) istrifluoroacetate is also specifically considered in the context of thepresent invention.

In the context of the present invention, it is also considered toprecipitate and isolate the compound of formula IV as its salt with H⁺_(n)X^(n−) from a solution containing the compound of formula IV asstarting material.

The precipitation and isolation of the salt of the compound of formulaIV with H⁺ _(n)X^(n−) can result in a further purification effect, asthe precipitated salt may contain less compound of formula III and/or offormula II than the mother liquor.

If the hydrogenation is performed under acidic conditions, theby-products present in the starting material and in the product may bepresent in their protonated form, or as a salt or solvate thereof.

The hydrogenation is generally performed at a temperature of from about35° C. to about 85° C., from about 40° C. to about 60° C., or from about40° C. to about 50° C.

In certain embodiments, the hydrogenation is performed with hydrogengas.

The hydrogenation using hydrogen gas is performed at a suitablepressure. In certain embodiments, the hydrogenation is performed at apressure of from about 17 psia (117.21 kPa) to about 100 psia (689.48kPa). In certain embodiments, it is performed at a pressure of fromabout 35 psia (241.32 kPa) to about 80 psia (551.58 kPa), e.g., at about60 psia (413.69 kPa).

The hydrogenation reaction may be run from about 0.5 minute to about 48hours, from about 1 minute to about 24 hours, from about 3 minutes toabout 22 hours, from about 5 minutes to about 18 hours, from about 7minutes to about 16 hours, from about 10 minutes to about 12 hours, fromabout 12 minutes to about 12 hours, from about 20 minutes to about 12hours, from about 30 minutes to about 4 hours, from about 2 hours toabout 6 hours, or from about 3 hours to about 6 hours. In certainembodiments, the hydrogenation reaction is run from about 1 hour toabout 48 hours.

In certain embodiments, the hydrogenation reaction is run for about 10minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours,about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5hours, about 5.5 hours, or about 6 hours.

In certain embodiments, the hydrogenation reaction is run for about 8hours, about 12 hours, about 16 hours, about 20 hours, or about 24hours.

In certain embodiments, the compound of formula IV or its salt orsolvate resulting from the hydrogenation will be precipitated andoptionally isolated from the reaction Said precipitation may take placewithin about 30 minutes, about 1 hour, about 1.5 hours, about 2 hours,about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about4.5 hours, about 5 hours, about 5.5 hours, or about 6 hours after thestart of the reaction. It may also take place within a longer period oftime, including within the complete reaction time. It may alsoalternatively or additionally take place during the period immediatelyfollowing the reaction period, e.g. during the venting period after ahydrogenation reaction using hydrogen gas.

An exemplary non-limiting list of hydrogenation catalysts includes,e.g., Pd/C, palladium-charcoal, a combination of diphenylsilane andPd/C, Pd(Ph₃P)/ZnCl₂, a combination of Pd/C with sodium hypophosphite(e.g., in aqueous acetic acid), Pt/C, Ru/C, Rh/C, PdO₂, PtO₂, zinc,magnesium. In certain embodiments, the catalyst is a palladium catalyst(e.g., Pd/C). In certain embodiments, the hydrogenation catalyst is nota metal, e.g., when the hydrogenation is a metal-free transferhydrogenation as described in Yang, J. W. et al., Angew. Chem. Int. Ed.(2004) 43:6660-6662.

In certain embodiments, a solid support catalyst is used, e.g., toensure reaction completion upon contact and/or potentially prevent orminimize the formation of any new compound of formula II from a compoundof formula III (e.g., formation of 14-hydroxymorphinone from8-hydroxyoxymorphone).

Transfer hydrogenation involves the use of a hydrogen transfer reagent.

Suitable hydrogen transfer reagents include HCO₂H, HCO₂H/HCO₂Na,HCO₂H/NEt₃, HCHO, H₂SO₄, HCO₂Na/NEt₃, H₂SO₄/NEt₃, H₃CSO₂NHNH₂/NEt₃, acombination thereof, and the like. Other hydrogen donors, likeisopropanol, indoline, cyclohexene, sodium borohydride,tetrahydroquinoline, 2,5-dihydrofuran, phosphoric acid, sodiumdithionite, and combinations thereof, might also be useful. In certainembodiments, the hydrogen transfer reagent is a dihydropyridine, e.g.,as described in Yang, J. W. et al., Angew. Chem. Int. Ed. (2004)43:6660-6662.

The hydrogenation may be done by a batch method or in a continuouslyflowing stream.

In certain embodiments, the hydrogenation is done by a batch method. Inan exemplary batch method, a catalyst (e.g., palladium on carbon) ischarged into a batch reactor. A solution or suspension of the compoundof formula V or the solvate thereof is added. If necessary, deionizedwater and acid are also added to the batch reactor. The batch reactor isthen sealed and hydrogenated (e.g., at 60 psia (413.69 kPa), and 40° C.or 55° C.) for a time period sufficient to complete hydrogenation (e.g.,for 24 hours). The catalyst is then removed by filtration.

The resulting compound of formula IV or salt or solvate thereof may thenbe precipitated by, e.g., addition of ammonium hydroxide. Alternatively,a precipitation can be achieved by adding an antisolvent to thefiltrate, or by preparing a supersaturated solution from which theresulting compound of formula IV or salt or solvate thereof isprecipitated, e.g. by cooling. The precipitated solids are thenoptionally washed and dried.

In certain embodiments, the hydrogenation reaction is conducted in acontinuously flowing stream. A reaction in a continuously flowing streamof the reactants allows for the transport of matter into and out of thereaction mixture as the reaction is taking place. Running the reactionin a continuously flowing stream allows, e.g., better control overreaction conditions (including, e.g., time, temperature, equivalents ofreagents, pressure, temperature, time of exposure of reactants tocatalysts, pH, etc.), and isolation and/or removal of the product havingformula IV from the reaction mixture as it is being formed and/or beforeany undesired compound is formed. In certain embodiments, the compoundof formula IV is removed from the reaction mixture as it is beingformed.

In certain embodiments, conducting the reaction in a continuouslyflowing stream allows for conducting the reaction at a temperature whichexceeds the boiling point of the solvent, because the pressure can besafely maintained.

In certain embodiments, conducting the reduction in a continuouslyflowing stream increases the yield of the reaction, increases the volumeefficiency of the reaction and/or decreases the number and amounts ofby-products formed during the reduction reaction, as the compound offormula IV is removed before it reacts with and/or is degraded by theremaining reactants.

In certain embodiments, the compound of formula V or solvate thereof isdissolved in a suitable solvent before and/or during the hydrogenationreaction. A suitable solvent may include or consist of, e.g., methanol,tetrahydrofuran, isopropanol, acetone, ethanol, 1-methoxy-2-propanol,2-ethoxyethanol, tert-amyl alcohol, isobutanol,2-methyl-tetrahydrofuran, n-propanol, 1-butanol, 2-butanol,tert-butanol, isopropyl acetate, and di(ethylene glycol) or a mixture ofwater with any one of the foregoing. In certain embodiments, thesuitable solvent includes or consists of methanol, tetrahydrofuran,isopropanol, acetone, ethanol, 1-methoxy-2-propanol, 2-ethoxyethanol,tert-amyl alcohol, or a mixture of water with any one of the foregoing,or consists of water.

In certain embodiments wherein preferably the compound of formula III isan 8-hydroxyoxymorphone and the compound of formula IV is oxymorphone,the suitable solvent is a 50:50 methanol:water mixture, 60:40methanol:water mixture, 70:30 methanol:water mixture, 80:20methanol:water mixture, 90:10 methanol:water mixture, 100:0methanol:water mixture, 50:50 ethanol:water mixture, 60:40 ethanol:watermixture, 70:30 ethanol:water mixture, 80:20 ethanol:water mixture, 90:10ethanol:water mixture, 100:0 ethanol:water mixture, 90:10tetrahydrofuran:water mixture, 100:0 tetrahydrofuran:water mixture,90:10 isopropanol:water mixture, 70:30 acetone:water mixture, 80:20acetone:water, or 90:10 acetone:water mixture. 8-Hydroxyoxymorphone ismore soluble in these mixtures than oxymorphone base and therefore mayremain in solution while the oxymorphone free base may be precipitatedby addition of a base at the end of the hydrogenation.

In certain embodiments, the suitable solvent comprises or consists of amixture of n-butanol and water.

In certain embodiments, the suitable solvent comprises or consists of amixture of 1-methoxy-2-propanol and water.

In certain embodiments, the suitable solvent is a mixture of1-methoxy-2-propanol and water, wherein the volume ratio of these twocomponents is preferably from 40:60 to 90:10 1-methoxy-2-propanol:water,e.g. 50:50 or 80:20. Preferably, the mixture contains more1-methoxy-2-propanol than water. In these mixtures, the salt of thecompound of formula IV with X advantageously precipitates during orafter the reduction reaction.

In certain embodiments, the suitable solvent comprises or consists ofwater.

In certain embodiments, the solvent may contain an effective amount ofacid to solubilize the compound of formula V or solvate thereof and toreduce conversion of the compound of formula V and/or compound offormula II to a compound of formula III during the reduction reaction.In certain embodiments, no acids are added to the reaction mixture.

In certain embodiments, the solvent used during the reduction reactionis different from the solvent used during the oxidation of a compound offormula I to the compound of formula V as described in Section II. Incertain other embodiments, the same solvents are used for reduction andoxidation.

Once the hydrogenation is completed, the compound of formula IV, salt orsolvate thereof may be precipitated. In certain embodiments, theprecipitation of the compound of formula IV, salt or solvate thereof isinitiated and/or enhanced by one or more of the following:

(i) adjusting (e.g., lowering) the temperature of the reaction mixtureto the precipitation temperature;(ii) addition of an antisolvent;(iii) addition of a seed crystal;(iv) changing the ionic strength of the reaction mixture (e.g., byaddition of a salt);(v) concentrating the reaction mixture;(vi) reducing or stopping agitation of the reaction mixture;or any other conventional method for initiating or enhancingprecipitation or crystallization.

When the temperature is adjusted to the precipitation temperature, thismeans that the precipitation of the compound of formula IV or the saltor solvate thereof is initiated and/or enhanced by adjusting thetemperature of the reaction mixture to or beyond a temperature at whichsaid compound precipitates (“precipitation temperature”). Thetemperature is either adjusted by performing the reaction at theprecipitation temperature, or by lowering the temperature of thereaction mixture during the reaction or after completion of thereaction.

In certain embodiments, the reaction mixture is adjusted to atemperature of ≦40° C. to initiate precipitation, i.e. the precipitationtemperature is ≦40° C. In certain embodiments, the precipitation isinitiated at a precipitation temperature of about −20° C., about −15°C., about −10° C., about −5° C., about 0° C., about 5° C., about 10° C.,about 15° C., about 17° C., about 19° C., about 21° C., about 23° C.,about 25° C., about 27° C., about 29° C., about 31° C., about 33° C.,about 35° C., about 37° C., or about 40° C.

In certain embodiments, the precipitation temperature is in a range offrom about −20° C. to about 40° C., preferably from about −10° C. toabout 40° C., more preferably from about −5° C. to about 35° C.

In certain embodiments, the precipitation temperature of the salt of thecompound of formula IV or a solvate of said salt is in a range of fromabout −10° C. to about 22° C., preferably from about −5° C. to about 10°C., more preferably from about −5° C. to about 5° C.

In certain embodiments, an antisolvent is used in addition to adjustingthe temperature to the precipitation temperature. In certainembodiments, e.g., when the compound of formula IV is oxymorphonesulfate or a solvate thereof, precipitation will also occur withoutadding an antisolvent.

In certain embodiments, precipitation is achieved by addition of asuitable organic or inorganic base until a suitable pH is reached. Asuitable pH may be a pH of ≧3, ≧4, ≧5, ≧6, or ≧7. A suitable base maycomprise or consist of NaOH, KOH, Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, HCO₂Na,CH₃CO₂Na, NEt₃, NH₄OH or any mixtures thereof.

In certain embodiments, the compound of formula IV is precipitated asits salt or a solvate thereof. In said salt, the anion is preferably thesame X^(n−) as in the starting material compound V. This precipitationmay be achieved by adding an antisolvent to a solution of the compoundof formula IV and its counter ion, or by preparing a supersaturatedsolution (e.g. by cooling or concentrating a reaction mixture) fromwhich the resulting salt of the compound of formula IV or solvatethereof is precipitated, e.g. by cooling beyond the precipitationtemperature or by adding a seed crystal. The precipitated solids arethen optionally washed and dried. In one aspect, this precipitation maybe achieved by adding one or more of acetone, 1-methoxy-2-propanol, andtert-butyl methyl ether to a reaction mixture. In a specific embodiment,tert-butyl methyl ether is added to a reaction mixture which already maycomprise water (which may be the sole solvent in the reaction mixture).In one aspect, this precipitation may be achieved by using a mixture ofwater and an antisolvent, in particular a mixture of water andtert-butyl methyl ether or a mixture of water, tetrahydrofuran, andtert-butyl methyl ether. Said mixture may be present as reaction solventduring the reduction reaction, or it may replace the reaction solventafter completion of the reduction reaction. The mixture can also beprepared by adding antisolvent after completion of the reaction.

Further suitable antisolvents may be the antisolvents described insection II, and the antisolvents described in Examples 5 and 6. I.e., asuitable antisolvent may comprise or consist of tert-butyl methyl ether,diethyl ether, hexane(s), tert-amyl alcohol, methanol, ethanol,n-propanol, isopropanol, 1-butanol, 2-butanol, tert-butanol, isobutanol,heptanes, xylenes, toluene, acetone, 2-butanone, ethyl acetate,isopropyl acetate, tetrahydrofuran, 2-methyl-tetrahydrofuran,1,2-dichloroethane, chloroform, dichloromethane, 1-methoxy-2-propanol,2-ethoxyethanol, 1,4-dioxane, methyl formate, methyl acetate, or amixture of two or more of any of the foregoing. The listed alcohols andethers are the preferred antisolvents. The most preferred antisolvent istert-butyl methyl ether.

The resulting precipitate may then be isolated, thus removing it fromthe mother liquor and advantageously further purifying the salt fromcompound of formula III and/or II which remains in the mother liquor.

Preferably, the resulting compound of formula IV, salt or solvatethereof comprises lower amounts of a compound of formula III and/orformula II (or salt or solvate thereof) as compared to compound offormula IV made by a process which does not involve the use of acompound of formula V as a starting material or intermediate material.

Compounds of formula IV and compositions comprising said compounds offormula IV which can be prepared via the process of present inventionare described, e.g., in Section VII below. The amounts of compounds offormula III and II which may be present in the compositions comprisingthe compounds of formula IV are described in Section VII below. Incertain embodiments, these compounds of formula IV or compositionscomprising the compounds of formula IV are the product of the processdescribed in the present section or in the subsequent Section VI.

In certain embodiments, the compositions comprising the compounds offormula IV which are the product of the process described in the presentsection or in the subsequent Section VI can be used as pharmaceuticalcompositions without further processing or purification steps, inparticular without further reduction (e.g., hydrogenation) steps.

In certain embodiments of this process starting from the compound offormula V or a solvate thereof, the compound of formula V is14-hydroxymorphinone sulfate or a solvate thereof, and the compound offormula IV is oxymorphone or a salt or solvate thereof.

In certain embodiments of this process starting from the compound offormula V or a solvate thereof, the compound of formula V is14-hydroxymorphinone sulfate or a solvate thereof, and the compound offormula IV is oxymorphone sulfate or a solvate thereof.

In certain embodiments of this process starting from the compound offormula V or a solvate thereof, the compound of formula V is14-hydroxymorphinone trifluoroacetate or a solvate thereof, and thecompound of formula IV is oxymorphone trifluoroacetate or a solvatethereof.

VI. Processes for Preparing a Compound of Formula IV Starting from aCompound of Formula I

Present invention further provides a process for preparing a compound offormula IV from a compound of formula I via a compound of formula V or asolvate thereof. In this process, the compound of formula V or solvatethereof serves as an intermediate. Said intermediate compound of formulaV or the solvate thereof may either be isolated or converted to acompound of formula IV or a salt or solvate thereof without furtherisolation. In certain preferred embodiments, said intermediate compoundof formula V or the solvate thereof is isolated before its conversion tothe compound of formula IV or a salt or solvate thereof.

Thus, present invention provides a process for preparing a compound offormula IV or a salt or solvate thereof from a compound of formula I ora salt or solvate thereof, the process comprising (Scheme 19):

In certain embodiments, the compound of formula V or solvate thereof isprecipitated and/or isolated in steps (c) and/or (d) before thereduction via steps (e) and (0.

In certain embodiments, said process will contain a further step, namely(g) isolating the compound of formula IV as its salt with H⁺ _(n)X^(n−)or as a solvate of said salt.

In certain embodiments, said process will contain a further step, namelythe liberation of the compound of formula II as a base from the compoundof formula V before the reduction step (f). In these embodiments, thecompound of formula II in its free base form is subsequently reduced instep (f) instead of the compound of formula V.

In certain embodiments, step (f) of the process results in apharmaceutically acceptable salt or solvate of the compound of formulaIV. In certain embodiments, step (f) of the process results not only insuch pharmaceutically acceptable salt or solvate of the compound offormula IV, but the complete resulting composition can be used aspharmaceutical composition without requiring further processing (e.g.,purification). In particular, it may be used without an additionalhydrogenation to remove by-products, e.g., compounds of formula II. Forexample, the process may result in an oxymorphone salt composition whichis suitable for incorporation into a dosage form, the oxymorphone saltcomposition being directly prepared from the reduction product of step(f) by a conversion which does not include a further/additionalhydrogenation step.

In certain embodiments, the salt or solvate of compound of formula IVwhich results from step (f) is not a pharmaceutically acceptable salt orsolvate.

In certain embodiments, the compound of formula IV or salt or solvatethereof resulting from step (f) may be converted into a pharmaceuticallyacceptable salt or solvate thereof in an additional step at the end ofthe process. Methods for such conversion are known in the art (e.g.,anion exchange).

In certain embodiments, the compound of formula V or solvate thereofwhich is an intermediate of the process will have the properties asdescribed in Section IV.

All elements of said process and the embodiments of said elements havealready been described above. Compounds of formula IV which can beprepared via the process, and the amounts of compounds of formula IIIand formula II which may be present in compositions comprising saidcompounds of formula IV are described in Section VII below. In certainembodiments, these compounds are the product of the process described inthe present section.

In the following, an exemplary embodiment of said process will bedescribed. Therein the compound of formula (I) is oripavine or a salt orsolvate thereof, the oxidation agent comprises or is performic acidformed in situ from hydrogen peroxide and formic acid, the acid H⁺_(n)X^(n−) in step (b) is sulfuric acid which is added to the reactionmixture, the compound having formula V is 14-hydroxymorphinone sulfateor a solvate thereof, and the compound of formula IV is oxymorphone or asalt or solvate thereof.

In another exemplary embodiment, the compound of formula (I) isoripavine or a salt or solvate thereof, the oxidation agent comprises oris performic acid formed in situ from hydrogen peroxide and formic acid,the acid H⁺ _(n)X^(n−) in step (b) is sulfuric acid which is added tothe reaction mixture, the compound having formula V is14-hydroxymorphinone sulfate or a solvate thereof, and the compound offormula IV is oxymorphone sulfate or a solvate thereof.

VII. Compounds of Formula IV

Present invention further provides a compound of formula IV:

wherein R¹ and R² are defined as above,or a salt or solvate thereof.

In certain embodiments, the compound of formula IV has one of thefollowing stereoconfigurations:

In preferred embodiments, the compound of formula IV has thestereoconfiguration represented below:

The compound of formula IV or salt or solvate thereof of presentinvention is obtainable or has been obtained by the processes describedin the preceding sections.

The salt or solvate of the compound of formula IV may be apharmaceutically acceptable salt or solvate. Such salts or solvates areknown in the art.

The compound of formula IV may be oxymorphone, noroxymorphone,nalfurafine, naltrexone, methylnaltrexone, naloxone, or a salt orsolvate thereof. In preferred embodiments, the compound of formula IV isselected from the group consisting of oxymorphone, noroxymorphone, saltsthereof and solvates thereof. In more preferred embodiments, it isselected from the group consisting of oxymorphone, salts thereof andsolvates thereof. In even more preferred embodiments, it is anoxymorphone salt. In even more preferred embodiments, it is oxymorphonehydrochloride.

In certain preferred embodiments, the compound of formula IV is providedas its salt with X^(n−) as anion. In more preferred embodiments, it isprovided as its sulfate salt or trifluoroacetate salt. In even morepreferred embodiments, it is provided as its sulfate salt. In a specificaspect, it is oxymorphone trifluoroacetate or a solvate thereof. In aspecific aspect, it is oxymorphone sulfate or a solvate thereof.

VII-A. Compositions Comprising Compound of Formula IV

The present invention further provides a composition comprising acompound of formula IV or an (optionally pharmaceutically acceptable)salt or solvate thereof.

Said composition may be the product of the process described in SectionVI.

Said composition may be a solid or a liquid. In certain embodiments, itis a solid. In certain embodiments, it is the precipitate containing thecompound of formula IV as described in Section VI.

In certain embodiments, the composition comprising the compound offormula IV or the (optionally pharmaceutically acceptable) salt orsolvate thereof additionally comprises a compound having the formulaIII:

wherein R¹ and R² are defined as in the compound of formula IV,or a salt or solvate thereof.

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the composition is less than about 2500 ppm,less than about 2250 ppm, less than about 2000 ppm, less than about 1750ppm, less than about 1500 ppm, or less than about 1250 ppm of thecompound of formula IV or salt or solvate thereof (HPLC peak arearatio).

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the composition is less than about 1000 ppm,less than about 750 ppm, less than about 500 ppm, or less than about 400ppm of the compound of formula IV or salt or solvate thereof (HPLC peakarea ratio).

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the composition is less than about 300 ppm,less than about 275 ppm, less than about 250 ppm, less than about 225ppm, less than about 200 ppm, less than about 175 ppm, less than about150 ppm, or less than about 125 ppm of the compound of formula IV orsalt or solvate thereof (HPLC peak area ratio).

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the composition is less than about 100 ppm,less than about 90 ppm, less than about 80 ppm, less than about 70 ppm,less than about 60 ppm, less than about 50 ppm, less than about 40 ppm,less than about 30 ppm, or less than about 20 ppm of the compound offormula IV or salt or solvate thereof (HPLC peak area ratio).

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the composition is less than about 10 ppm,less than about 8 ppm, less than about 6 ppm, less than about 4 ppm, orless than about 2 ppm of the compound of formula IV or salt or solvatethereof (HPLC peak area ratio).

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the composition is less than about 1 ppm,less than about 0.8 ppm, less than about 0.6 ppm, less than about 0.4ppm, less than about 0.3 ppm, less than about 0.2 ppm, or less thanabout 0.1 ppm of the compound of formula IV or salt or solvate thereof(e.g., the amount of 8-hydroxyoxymorphone is from about 0.1 ppm to about0.7 ppm of the 14-hydroxymorphinone sulfate) (HPLC peak area ratio).

In certain embodiments, the composition does not contain compound offormula III.

In certain embodiments, the amount of the compound of formula III orsalt or solvate thereof in the composition has a lower limit of about0.05 ppm of the compound of formula IV or salt or solvate thereof (HPLCpeak area ratio). In certain embodiments, the lower limit is about 0.1ppm, about 0.3 ppm, about 0.5 ppm, about 0.7 ppm, about 1 ppm, about 1.5ppm, about 2 ppm, or about 3 ppm. For example, the amount of thecompound of formula III or salt or solvate thereof in the compositionmay range from about 0.05 ppm to 1 ppm in a certain embodiment, and fromabout 1 ppm to about 10 ppm in a certain other embodiment.

In certain embodiments, the compound of formula IV is oxymorphone or asalt or solvate thereof, and the amount of 8-hydroxyoxymorphone or saltor solvate thereof in the composition is less than about 300 ppm, lessthan about 275 ppm, less than about 250 ppm, less than about 225 ppm,less than about 200 ppm, less than about 175 ppm, less than about 150ppm, less than about 125 ppm, less than about 100 ppm, less than about80 ppm, less than about 60 ppm, less than about 40 ppm, less than about30 ppm, or less than about 20 ppm of the oxymorphone (HPLC peak arearatio). In certain embodiments, it is less than about 10 ppm, less thanabout 8 ppm, less than about 6 ppm, less than about 4 ppm, less thanabout 2 ppm, less than about 1 ppm, less than about 0.8 ppm, less thanabout 0.6 ppm, less than about 0.4 ppm, less than about 0.3 ppm, lessthan about 0.2 ppm, or less than about 0.1 ppm of the oxymorphone (HPLCpeak area ratio). In certain embodiments, the oxymorphone does notcontain 8-hydroxyoxymorphone.

In certain embodiments, the composition comprises from about 0.05 ppm toabout 2500 ppm, from about 0.05 to about 2250 ppm, from about 0.1 ppm toabout 2000 ppm, from about 0.3 to about 1750 ppm, from about 0.5 ppm toabout 1500 ppm, or from about 1 ppm to about 1250 ppm compound offormula III or a salt or solvate thereof in relation to the compound offormula IV or salt or solvate thereof (HPLC peak area ratio).

In certain embodiments, the composition comprises from about 0.05 ppm toabout 1000 ppm, from about 0.1 ppm to about 800 ppm, from about 0.1 ppmto about 700 ppm, from about 0.2 ppm to about 600 ppm, from about 0.3ppm to about 500 ppm, or from about 0.5 ppm to about 400 ppm compound offormula III or salt or solvate thereof in relation to the compound offormula IV or salt or solvate thereof.

In certain embodiments, the composition comprises from about 0.05 ppm toabout 350 ppm, from about 0.1 ppm to about 300 ppm, from about 0.2 ppmto about 275 ppm, from about 0.3 ppm to about 250 ppm, from about 0.4ppm to about 225 ppm, or from about 0.5 ppm to about 200 ppm compound offormula III or salt or solvate thereof in relation to compound IV orsalt or solvate thereof.

In certain embodiments, the composition comprising the compound offormula IV or the (optionally pharmaceutically acceptable) salt orsolvate thereof additionally comprises a compound having the formula II

wherein R¹ and R² are defined as in the compound of formula IV,or a salt or solvate thereof.

The amount of the compound having the formula II or salt or solvatethereof in relation to the amount of the compound having the formula IVor salt or solvate thereof in the composition may in certain embodimentsbe less than about 500 ppm, less than about 250 ppm, less than about 200ppm, less than about 100 ppm, less than about 50 ppm or less than about40 ppm (HPLC peak area ratio). In certain embodiments, it may be lessthan about 30 ppm, less than about 25 ppm, less than about 20 ppm, lessthan about 15 ppm, less than about 10 ppm, less than about 5 ppm, orless than about 2.5 ppm (HPLC peak area ratio). In certain embodiments,it may be less than about 1 ppm, less than about 0.8 ppm, less thanabout 0.6 ppm, less than about 0.6 ppm, less than about 0.4 ppm, lessthan about 0.2 ppm, or less than about 0.1 ppm (HPLC peak area ratio).In certain embodiments, the composition does not contain compound offormula II.

In certain embodiments, the amount of the compound of formula II or saltor solvate thereof in the composition has a lower limit of about 0.05ppm of the compound of formula IV or salt or solvate thereof (HPLC peakarea ratio). In certain embodiments, the lower limit is about 0.1 ppm,about 0.3 ppm, about 0.5 ppm, about 0.7 ppm, about 1 ppm, about 1.5 ppm,about 2 ppm, or about 3 ppm. For example, the amount of the compound offormula II or salt or solvate thereof in the composition may range fromabout 0.05 ppm to 1 ppm in a certain embodiment, and from about 1 ppm toabout 10 ppm in a certain other embodiment.

The composition in certain embodiments comprises from about 0.05 ppm toabout 500 ppm, from about 0.05 ppm to about 250 ppm, from about 0.05 ppmto about 200 ppm, from about 0.05 ppm to about 100 ppm, from about 0.05ppm to about 50 ppm, from about 0.05 ppm to about 25 ppm, from about0.05 ppm to about 10 ppm, from about 0.05 ppm to about 5 ppm, or fromabout 0.05 ppm to about 1 ppm compound of formula II or salt or solvatethereof in relation to compound IV or salt or solvate thereof.

In certain embodiments wherein the compound of formula IV is oxymorphoneor a salt or solvate thereof and wherein the compound of formula II is14-hydroxymorphinone or a salt or solvate thereof, the amount of thecompound having the formula II in relation to the amount of the compoundhaving the formula IV in the composition is less than about 200 ppm,less than about 175 ppm, less than about 150 ppm, less than about 125ppm, less than about 100 ppm, less than about 80 ppm, less than about 60ppm, less than about 40 ppm, less than about 30 ppm, less than about 20ppm, or less than about 10 ppm, or less than about 5 ppm of the compoundof formula IV (HPLC peak area ratio). In certain embodiments, thecomposition does not contain 14-hydroxymorphinone or a salt or solvatethereof.

The composition comprising the compound of formula IV or salt or solvatethereof may also additionally comprise a combination of a compound offormula III with a compound of formula II, preferably within the limitsfor the single compounds II and III as described in the precedingparagraphs.

In one embodiment, said compound of formula IV is oxymorphone or a saltor solvate thereof, said compound having the formula III is8-hydroxyoxymorphone or a salt or solvate thereof, and said compoundhaving the formula II is 14-hydroxymorphinone or a salt or solvatethereof. The compound of formula IV may be an oxymorphone salt. In oneembodiment, it may be oxymorphone hydrochloride.

In another embodiment, said compound of formula IV is noroxymorphone ora salt or solvate thereof, said compound having the formula III is8-hydroxynoroxymorphone or a salt or solvate thereof, and said compoundhaving the formula II is 14-hydroxynoroxymorphinone or a salt or solvatethereof.

In another embodiment, said compound of formula IV is naltrexone or asalt or solvate thereof, said compound having the formula III is8-hydroxynaltrexone, and said compound having the formula II is17-cyclopropylmethyl-14-hydroxynormorphinone.

In another embodiment, said compound of formula IV is methylnaltrexoneor a salt or solvate thereof, said compound having the formula III is17-cyclopropylmethyl-8,14-dihydroxy-17-methyl-normorphinone, and saidcompound having the formula II is17-cyclopropylmethyl-14-hydroxy-17-methyl-normorphinone.

In certain embodiments, the composition comprising the compound offormula IV or the (optionally pharmaceutically acceptable) salt orsolvate thereof additionally comprises both a compound of formula II anda compound of formula III. In certain embodiments, the compositioncomprises a combined amount of compound of formula II and compound offormula III which is less than about 3000 ppm, less than about 2750 ppm,less than about 2500 ppm, less than about 2250 ppm, less than about 2000ppm, less than about 1750 ppm, less than about 1500 ppm, or less thanabout 1250 in relation to the amount of the compound of formula IV (HPLCpeak area ratio).

In certain embodiments, the combined amount of the compound of formulaII and III in the composition is less than about 1000 ppm, less thanabout 750 ppm, less than about 500 ppm, less than about 400 ppm, lessthan about 300 ppm, or less than about 275 ppm in relation to the amountof the compound of formula IV (HPLC peak area ratio).

In certain embodiments, the combined amount of the compound of formulaII and III in the composition is less than about 250 ppm, less thanabout 225 ppm, less than about 200 ppm, less than about 175 ppm, lessthan about 150 ppm, or less than about 125 ppm in relation to the amountof the compound of formula IV (HPLC peak area ratio).

In certain embodiments, the combined amount of the compound of formulaII and III in the composition is less than about 100 ppm, less thanabout 90 ppm, less than about 80 ppm, less than about 70 ppm, less thanabout 60 ppm, less than about 50 ppm, less than about 40 ppm, less thanabout 30 ppm, or less than about 20 ppm in relation to the amount of thecompound of formula IV (HPLC peak area ratio).

In certain embodiments, the combined amount of the compound of formulaII and III in the composition is less than about 10 ppm, les than about8 ppm, less than about 6 ppm, less than about 4 ppm, or less than about2 ppm in relation to the amount of the compound of formula IV (HPLC peakarea ratio).

In certain embodiments, the combined amount of the compound of formulaII and III in the composition is less than about 1 ppm, less than about0.8 ppm, less than about 0.6 ppm, less than about 0.4 ppm, less thanabout 0.3 ppm, less than about 0.2 ppm, or less than about 0.1 ppm inrelation to the amount of the compound of formula IV (HPLC peak arearatio).

In certain embodiments, the composition does not contain compound offormula II and III.

In certain embodiments, the combined amount of the compound of formulaII and III in the composition has a lower limit of about 0.05 ppm of thecompound of formula IV (HPLC peak area ratio). In certain embodiments,the lower limit is about 0.1 ppm, about 0.3 ppm, about 0.5 ppm, about0.7 ppm, about 1 ppm, about 1.5 ppm, about 2 ppm, or about 3 ppm inrelation to the amount of the compound of formula IV (HPLC peak arearatio).

In certain embodiments, the composition comprises less than about 200ppm, less than about 150 ppm, less than about 100 ppm, or less thanabout 50 ppm of a compound of formula II or a salt or solvate thereof,and/or less than about 1000 ppm, less than about 750 ppm, less thanabout 500 ppm, less than about 300 ppm, less than about 200 ppm, or lessthan about 100 ppm of a compound of formula III or a salt or solvatethereof.

In certain embodiments, the composition comprises less than about 100ppm, less than about 50 ppm, less than about 25 ppm, less than about 20ppm, less than about 15 ppm, or less than about 10 ppm of a compound offormula II or a salt or solvate thereof, and/or less than about 300 ppm,less than about 200 ppm, less than about 100 ppm, less than about 50ppm, less than about 25 ppm, or less than about 10 ppm of a compound offormula III or a salt or solvate thereof.

In certain embodiments, the composition comprises less than about 25ppm, less than about 20 ppm, less than about 15 ppm, less than about 10ppm, less than about 5 ppm, or less than about 1 ppm of a compound offormula II or a salt or solvate thereof, and/or less than about 100 ppm,less than about 50 ppm, less than about 25 ppm, less than about 10 ppm,or less than about 5 ppm of a compound of formula III or a salt orsolvate thereof.

In certain embodiments, the composition comprises less than about 10ppm, less than about 5 ppm, less than about 4 ppm, less than about 3ppm, less than about 2 ppm, less than about 1 ppm, or less than about0.5 ppm of a compound of formula II or a salt or solvate thereof, and/orless than about 10 ppm, less than about 5 ppm, less than about 3 ppm,less than about 2 ppm, less than about 1 ppm, or less than about 0.5 ppmof a compound of formula III or a salt or solvate thereof.

In certain embodiments, the compound of formula IV in the composition isoxymorphone or a salt or solvate thereof, and the compositionadditionally comprises (i) 8-hydroxyoxymorphone or a salt or solvatethereof, and/or (ii) 14-hydroxymorphinone or a salt or solvate thereof,wherein the amount of the 8-hydroxyoxymorphone is less than about 300ppm, less than about 275 ppm, less than about 250 ppm, less than about225 ppm, less than about 200 ppm, less than about 175 ppm, less thanabout 150 ppm, less than about 125 ppm, less than about 100 ppm, lessthan about 80 ppm, less than about 60 ppm, less than about 40 ppm, lessthan about 30 ppm, less than about 20 ppm, less than about 10 ppm, lessthan about 8 ppm, less than about 6 ppm, less than about 4 ppm, lessthan about 2 ppm, less than about 1 ppm, less than about 0.8 ppm, lessthan about 0.6 ppm, less than about 0.4 ppm, less than about 0.3 ppm,less than about 0.2 ppm, or less than about 0.1 ppm of the oxymorphone(HPLC peak area ratio; e.g., from about 0.2 ppm to about 50 ppm of theoxymorphone), and the amount of the 14-hydroxymorphinone is less thanabout 200 ppm, less than about 175 ppm, less than about 150 ppm, lessthan about 125 ppm, less than about 100 ppm, less than about 80 ppm,less than about 60 ppm, less than about 40 ppm, less than about 30 ppm,less than about 20 ppm, or less than about 10 ppm, or less than about 5ppm of the compound of formula IV (HPLC peak area ratio; e.g., fromabout 0.1 ppm to about 15 ppm, or from about 0.2 ppm to about 2 ppm ofthe oxymorphone). In certain embodiments, the compound of formula IV isoxymorphone free base.

In certain embodiments, the compound of formula IV in the composition isan oxymorphone salt, and the composition additionally comprises (i)8-hydroxyoxymorphone or a salt or solvate thereof, and/or (ii)14-hydroxymorphinone or a salt or solvate thereof, wherein the amount ofthe 8-hydroxyoxymorphone is less than about 100 ppm, less than about 80ppm, less than about 60 ppm, less than about 40 ppm, less than about 30ppm, less than about 20 ppm, less than about 10 ppm, less than about 5ppm, or less than about 2 ppm of the oxymorphone salt (HPLC peak arearatio; e.g., from about 0.1 ppm to about 9 ppm of the oxymorphone salt),and the amount of the 14-hydroxymorphinone is less than about 50 ppm,less than about 25 ppm, less than about 10 ppm, less than about 5 ppm,or less than about 2 ppm of the oxymorphone salt (HPLC peak area ratio).In certain embodiments, the oxymorphone salt is oxymorphonehydrochloride.

In certain embodiments, other opioids are contained in the compositioncomprising the compound of formula IV or salt or solvate thereof, whichare contained instead of or in addition to a compound of formula IIand/or a compound of formula III or respective salts or solvatesthereof.

In certain embodiments, the compound of formula IV in the composition isoxymorphone or a salt or solvate thereof, and the composition may notonly contain 8-hydroxyoxymorphone and/or 14-hydroxymorphinone asdescribed above, but also in addition one or more of the followingcompounds: oxymorphone N-oxide, hydromorphone, oxycodone,pseudo-oxymorphone (i.e., 2,2′-bisoxymorphone), 6α-oxymorphol (i.e.,14-hydroxydihydromorphine), 6β-oxymorphol (i.e.,14-hydroxydihydroisomorphine), 10-hydroxyoxymorphone,14-hydroxymorphine, 14-hydroxyisomorphine, 14-hydroxymorphinone N-oxide,oripavine, 8,14-dihydrooripavine, and 10-ketooxymorphone.

The oxymorphone N-oxide, if present, is in certain embodimentspreferably present in an amount of not more than about 2000 ppm, morepreferably not more than about 1000 ppm of the oxymorphone or salt orsolvate thereof. The oxycodone, if present, is in certain embodimentspreferably present in an amount of not more than about 2000 ppm, morepreferably not more than about 1000 ppm, more preferably not more thanabout 500 ppm of the oxymorphone or salt or solvate thereof. The2,2′-bisoxymorphone, if present, is in certain embodiments preferablypresent in an amount of not more than about 2000 ppm, more preferablynot more than about 1000 ppm, more preferably not more than about 500ppm of the oxymorphone or salt or solvate thereof. The10-ketooxymorphone, if present, is preferably present in an amount ofnot more than about 2000 ppm, more preferably not more than about 1000ppm of the oxymorphone or salt thereof. The 6α-oxymorphol, if present,is preferably present in an amount of not more than about 2000 ppm, morepreferably not more than about 1000 ppm of the oxymorphone or saltthereof. The 6β-oxymorphol, if present, is preferably present in anamount of not more than about 2000 ppm, more preferably not more thanabout 1000 ppm of the oxymorphone or salt thereof. The10-hydroxyoxymorphone, if present, is preferably present in an amount ofnot more than about 2000 ppm, more preferably not more than about 1500ppm, more preferably not more than about 1000 ppm of the oxymorphone orsalt thereof. The hydromorphone, if present, is preferably present in anamount of not more than about 2000 ppm, more preferably not more thanabout 1500 ppm, more preferably not more than about 1000 ppm of theoxymorphone or salt thereof.

Compositions comprising a compound of formula IV or salt or solvatethereof, or comprising a mixture or combination of said compound offormula IV or salt or solvate thereof with another opioid, or comprisinga mixture or combination of two or more of said compounds of formula IVor salts or solvates thereof are also considered as embodiments of thepresent invention. Such compositions may be pharmaceutical compositionsor dosage forms as described below. For example, such composition may bea pharmaceutical composition or dosage form comprising a mixture orcombination of oxymorphone and naloxone, wherein both of said compoundsor one of said compounds are/is a compound of formula IV or a(pharmaceutically acceptable) salt or solvate thereof.

VIII. Use of the Compound of Formula IV and the Composition Comprisingthe Compound of Formula IV VIII-A. Use in a Medicament

The present invention further provides the use of a compound of formulaIV or a pharmaceutically acceptable salt or solvate thereof as API of amedicament.

For this use, the compound of formula IV or the pharmaceuticallyacceptable salt or solvate thereof may be the compound as described inSection VII.

For this use, the compound of formula IV or the pharmaceuticallyacceptable salt or solvate thereof may be used in the form of thecomposition as described in Section VII-A.

For this use, the compound of formula IV or the pharmaceuticallyacceptable salt or solvate thereof may be used in a dosage form asdescribed in Section IX.

For this use, the medicament may be for treating a medical conditionselected from the group consisting of pain, addiction, cough,constipation, diarrhea, insomnia associated with and/or caused by pain,cough or addiction, depression associated with and/or resulting frompain, cough or addiction, or a combination of two or more of theforegoing conditions. In particular, said condition may be pain.

The present invention also provides a method for treating an animal,preferably a mammal (e.g., a human), (in the following: “a patient”)using the compound of formula. IV or a pharmaceutically acceptable saltor solvate thereof. Said treatment may be of any medical condition whichis conventionally treated by administration of the compound of formulaIV or a pharmaceutically acceptable salt or solvate thereof to apatient.

Said medical condition may be pain, addiction, cough, constipation,diarrhea, insomnia associated with and/or caused by pain, cough oraddiction, depression associated with and/or resulting from pain, coughor addiction, or a combination of two or more of the foregoingconditions. In particular, said condition may be pain.

For this method of treatment, the compound of formula IV or thepharmaceutically acceptable salt or solvate thereof may be the compoundas described in Section VII.

For this method of treatment, the compound of formula IV or thepharmaceutically acceptable salt or solvate thereof may be used in theform of the composition as described in Section VII-A.

For this method of treatment, the compound of formula IV or thepharmaceutically acceptable salt or solvate thereof may be used in adosage form as described in Section IX.

VIII-B. Other Uses

The compound of formula IV or an (optionally pharmaceuticallyacceptable) salt or solvate thereof, and the composition comprising saidcompound according to the present invention, may also be used asfollows:

In certain embodiments, the compound of formula IV or (optionallypharmaceutically acceptable) salt or solvate thereof, or the compositioncomprising said compound, is used as an intermediate or startingmaterial for preparing the compound IV in its free form or for preparinganother salt or solvate of said compound of formula IV, e.g., forpreparing a(nother) pharmaceutically acceptable salt or solvate of saidcompound of formula IV. For example, when the compound of formula IV isoxymorphone, it may be used for preparing oxymorphone hydrochloride. Forexample, when the compound of formula IV is provided as oxymorphonesulfate, it may be used for preparing oxymorphone hydrochloride or forpreparing oxymorphone in its free form. Processes for preparing saidother salt or solvate which involve a process or compound as describedabove in the detailed description are also embodiments of the presentinvention.

In certain embodiments, the compound of formula IV or (optionallypharmaceutically acceptable) salt or solvate thereof, or the compositioncomprising said compound, is used as an intermediate or startingmaterial for preparing another opioid or a pharmaceutically acceptablesalt or solvate thereof or a prodrug thereof, and/or for preparing amedicament containing the compound of formula IV or a pharmaceuticallyacceptable salt or solvate thereof, or containing another opioid or apharmaceutically acceptable salt or solvate thereof. For example, whenthe compound of formula IV is oxymorphone, it may be used as startingmaterial for preparing oxycodone, naloxone, noroxymorphone, naltrexone,methyl naltrexone, nalmafine, or nalfurafine. Processes for preparingsaid other opioids which involve a process or compound as describedabove in the detailed description are also embodiments of the presentinvention.

IX. Dosage Forms

Dosage forms in accordance with the present invention comprise one ormore of the compounds or compositions described above and one or morepharmaceutically acceptable excipients. The dosage forms may or may notbe abuse-resistant.

Those compounds, compositions, salts or solvates according to thepresent invention which are or contain an active pharmaceuticalingredient, in particular the opioids and compounds of formula IV whichare described in Section VII, the pharmaceutically acceptable salts andsolvates thereof (e.g., oxymorphone and pharmaceutically acceptablesalts and solvates thereof), and the compositions which are described inSection VII-A which contain a compound of formula IV or apharmaceutically acceptable salt or solvate thereof, can be comprised ina pharmaceutical dosage form or medicament. Other opioids made fromcompounds, salts or solvates according to the present invention can alsobe comprised in a pharmaceutical dosage form or medicament. Prodrugs ofthe opioids described herein can also be comprised in a pharmaceuticaldosage form or medicament. Such dosage forms and medicaments are also anembodiment of the present invention.

In addition to said active pharmaceutical ingredient, said dosage formscomprise one or more pharmaceutically acceptable excipients.

A pharmaceutical dosage form of the present invention may comprise (i)an opioid according to present invention or a pharmaceuticallyacceptable salt or solvate thereof, and (ii) one or morepharmaceutically acceptable excipients. In particular, a pharmaceuticaldosage form of the present invention may comprise (i) oxymorphone or anoxymorphone salt or solvate, noroxymorphone or a noroxymorphone salt orsolvate, nalfurafine or a nalfurafine salt or solvate, naltrexone or analtrexone salt or solvate, methylnaltrexone or a methylnaltrexone saltor solvate, naloxone or a naloxone salt or solvate, nalmefene or analmefene salt or solvate, all as described above, and (ii) one or morepharmaceutically acceptable excipients.

In certain embodiments, the dosage form comprises oxymorphone or apharmaceutically acceptable salt or solvate thereof, noroxymorphone or apharmaceutically acceptable salt or solvate thereof, nalfurafine or apharmaceutically acceptable salt or solvate thereof, naltrexone or apharmaceutically acceptable salt or solvate thereof, methylnaltrexone ora pharmaceutically acceptable salt or solvate thereof, naloxone or apharmaceutically acceptable salt or solvate thereof, or nalmefene or apharmaceutically acceptable salt or solvate thereof, wherein saidcompounds have the properties as described in Section VII, and/or arecontained in a composition as described in Section VII-A, and/or havebeen prepared according to a process of the present invention.

In certain embodiments, the dosage form comprises oxymorphone or apharmaceutically acceptable salt or solvate thereof, wherein saidcompounds have the properties as described in Section VII, and/or arecontained in a composition as described in Section VII-A, and/or havebeen prepared according to a process of the present invention. In oneembodiment, the oxymorphone salt is oxymorphone hydrochloride.

In certain embodiments, the dosage form comprises a combination of twoor more of the active pharmaceutical ingredients listed in the fourpreceding paragraphs, wherein at least one of said agents has theproperties as described in Section VII, and/or is contained in acomposition as described in Section VII-A, and/or has been preparedaccording to a process of the present invention. In certain embodiments,the dosage form comprises a combination of oxymorphone or a salt orsolvate thereof which has the properties as described in Section VII,and/or is contained in a composition as described in Section VII-A,and/or has been prepared according to a process of the presentinvention, with another opioid. In certain embodiments, the dosage formcomprises a combination of oxymorphone or a salt or solvate thereofwhich has the properties as described in Section VII, and/or iscontained in a composition as described in Section VII-A, and/or hasbeen prepared according to a process of the present invention, with anopioid receptor antagonist. For example, a dosage form of the presentinvention may comprise a combination of oxymorphone or apharmaceutically acceptable salt or solvate thereof (such as oxymorphonehydrochloride) and naloxone or a pharmaceutically acceptable salt orsolvate thereof or a pharmaceutically acceptable salt or solvate thereof(such as naloxone hydrochloride).

In certain embodiments, the dosage form is selected from the groupconsisting of oral dosage forms (e.g., tablets, capsules, suspensions,solutions, etc.), injectable dosage forms, rectal dosage forms (e.g.,suppositories), and transdermal dosage forms (e.g., patches).

In certain embodiments, a pharmaceutical composition or dosage formcomprising at least one or a combination of the active pharmaceuticalingredients according to the present invention additionally comprises acompound of formula II and/or a compound of formula III.

In certain embodiments, a pharmaceutical composition or dosage formcomprises at least one or a combination of the active pharmaceuticalingredients according to the present invention and additionallycomprises a compound of formula II and/or a compound of formula III,wherein the combined amount of compound of formula II and compound offormula III is less than about 3000 ppm, less than about 2750 ppm, lessthan about 2500 ppm, less than about 2250 ppm, less than about 2000 ppm,less than about 1750 ppm, less than about 1500 ppm, or less than about1250 in relation to the amount of the active pharmaceutical ingredient.

In certain embodiments, the combined amount of the compound of formulaII and III in the pharmaceutical composition or dosage form is less thanabout 1000 ppm, less than about 750 ppm, less than about 500 ppm, lessthan about 400 ppm, less than about 300 ppm, or less than about 275 ppmin relation to the amount of the active pharmaceutical ingredient.

In certain embodiments, the combined amount of the compound of formulaII and III in the pharmaceutical composition or dosage form is less thanabout 250 ppm, less than about 225 ppm, less than about 200 ppm, lessthan about 175 ppm, less than about 150 ppm, or less than about 125 ppmin relation to the amount of the active pharmaceutical ingredient.

In certain embodiments, the combined amount of the compound of formulaII and III in the pharmaceutical composition or dosage form is less thanabout 100 ppm, less than about 90 ppm, less than about 80 ppm, less thanabout 70 ppm, less than about 60 ppm, less than about 50 ppm, less thanabout 40 ppm, less than about 30 ppm, or less than about 20 ppm inrelation to the amount of the active pharmaceutical ingredient.

In certain embodiments, the combined amount of the compound of formulaII and III in the pharmaceutical composition or dosage form is less thanabout 10 ppm, less than about 8 ppm, less than about 6 ppm, less thanabout 4 ppm, or less than about 2 ppm in relation to the amount of theactive pharmaceutical ingredient.

In certain embodiments, the combined amount of the compound of formulaII and III in the pharmaceutical composition or dosage form is less thanabout 1 ppm, less than about 0.8 ppm, less than about 0.6 ppm, less thanabout 0.4 ppm, less than about 0.3 ppm, less than about 0.2 ppm, or lessthan about 0.1 ppm in relation to the amount of the activepharmaceutical ingredient.

In certain embodiments, the pharmaceutical composition or dosage formdoes not contain compound of formula II and III.

In certain embodiments, the combined amount of the compound of formulaII and III in the pharmaceutical composition or dosage form has a lowerlimit of about 0.05 ppm of the active pharmaceutical ingredient. Incertain embodiments, the lower limit is about 0.1 ppm, about 0.3 ppm,about 0.5 ppm, about 0.7 ppm, about 1 ppm, about 1.5 ppm, about 2 ppm,or about 3 ppm in relation to the amount of the active pharmaceuticalingredient.

In certain embodiments wherein the API is a compound which is not acompound of formula II or a salt or solvate thereof, a pharmaceuticalcomposition or dosage form comprising at least one or a combination ofthe active pharmaceutical ingredients according to present inventioncomprises less than 500 ppm, less than about 250 ppm, less than about200 ppm, less than about 100 ppm, less than about 50 ppm or less thanabout 40 ppm of a compound of formula II (HPLC peak area ratio). Incertain embodiments, it may be less than about 30 ppm, less than about25 ppm, less than about 20 ppm, les than about 15 ppm, less than about10 ppm, less than about 5 ppm, or less than about 2.5 ppm (HPLC peakarea ratio). In certain embodiments, it may be less than about 1 ppm,less than about 0.8 ppm, less than about 0.6 ppm, less than about 0.6ppm, less than about 0.4 ppm, less than about 0.2 ppm, or less thanabout 0.1 ppm (HPLC peak area ratio).

In certain embodiments, a pharmaceutical composition or dosage formcomprising at least one or a combination of the active pharmaceuticalingredients according to present invention comprises less than about 200ppm, less than about 150 ppm, less than about 100 ppm, or less thanabout 50 ppm of a compound of formula II or a salt or solvate thereof,and/or less than about 1000 ppm, less than about 750 ppm, less thanabout 500 ppm, less than about 300 ppm, less than about 200 ppm, or lessthan about 100 ppm of a compound of formula III or a salt or solvatethereof.

In certain embodiments, a pharmaceutical composition or dosage formcomprising at least one or a combination of the active pharmaceuticalingredients according to present invention comprises less than about 100ppm, less than about 50 ppm, less than about 25 ppm, less than about 20ppm, less than about 15 ppm, or less than about 10 ppm of a compound offormula II or a salt or solvate thereof, and/or less than about 300 ppm,less than about 200 ppm, less than about 100 ppm, less than about 50ppm, less than about 25 ppm, or less than about 10 ppm of a compound offormula III or a salt or solvate thereof.

In certain embodiments, a pharmaceutical composition or dosage formcomprising at least one or a combination of the active pharmaceuticalingredients according to present invention comprises less than about 25ppm, less than about 20 ppm, less than about 15 ppm, less than about 10ppm, less than about 5 ppm, or less than about 1 ppm of a compound offormula II or a salt or solvate thereof, and/or less than about 100 ppm,less than about 50 ppm, less than about 25 ppm, less than about 10 ppm,or less than about 5 ppm of a compound of formula III or a salt orsolvate thereof.

In certain embodiments, a pharmaceutical composition or dosage formcomprising at least one or a combination of the active pharmaceuticalingredients according to present invention comprises less than about 10ppm, less than about 5 ppm, less than about 4 ppm, less than about 3ppm, less than about 2 ppm, less than about 1 ppm, or less than about0.5 ppm of a compound of formula II or a salt or solvate thereof, and/orless than about 10 ppm, less than about 5 ppm, less than about 3 ppm,less than about 2 ppm, less than about 1 ppm, or less than about 0.5 ppmof a compound of formula III or a salt or solvate thereof.

In certain embodiments, the dosage form comprises as an API oxymorphoneor a pharmaceutically acceptable salt or solvate thereof, noroxymorphoneor a pharmaceutically acceptable salt or solvate thereof, nalfurafine ora pharmaceutically acceptable salt or solvate thereof, naltrexone or apharmaceutically acceptable salt or solvate thereof, methylnaltrexone ora pharmaceutically acceptable salt or solvate thereof, naloxone or apharmaceutically acceptable salt or solvate thereof, or nalmefene or apharmaceutically acceptable salt or solvate thereof, wherein saidcompound has the properties as described in Section VII and/or has beenprepared according to a process of the present invention, or acombination of two or more said compounds, wherein at least one of saidcompounds has the properties as described in Section VII and/or has beenprepared according to a process of the present invention. In certainpreferred embodiments, the dosage form comprises oxymorphone or apharmaceutically acceptable oxymorphone salt, e.g., oxymorphonehydrochloride, as an active pharmaceutical ingredient.

In said embodiments, the dosage form may be selected from the groupconsisting of oral dosage forms (e.g., tablets, capsules, suspensions,solutions, etc.), injectable dosage forms, rectal dosage forms (e.g.,suppositories), and transdermal dosage forms (e.g., patches). Dosageforms for oral administration may be presented as tablets, capsules,liquid formulations, troches, lozenges, powders, granules,microparticles (e.g., microcapsules, microspheres and the like), orbuccal tablets.

In certain embodiments, oral dosage forms of the present invention maybe in the form of tablets (sustained release and/or immediate release),solutions, suspensions, etc.

Oral dosage forms can provide a controlled release (sustained release ordelayed release) or an immediate release of the active pharmaceuticalingredient. One of the conventional excipients may be a pharmaceuticallyacceptable carrier. Suitable pharmaceutically acceptable carriersinclude but are not limited to, e.g., alcohols, gum arabic, vegetableoils, benzyl alcohols, polyethylene glycols, gelate, carbohydrates suchas lactose, amylose or starch, magnesium stearate, talc, silicic acid,viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose,polyvinylpyrrolidone, etc.. The dosage form may further comprise aninert diluent such as lactose; granulating and disintegrating agentssuch as cornstarch; binding agents such as starch; and lubricatingagents such as magnesium stearate. The tablets may be uncoated or theymay be coated by known techniques for elegance or to provide acontrolled release of the drug (a sustained release, a delayed releaseor a pulsatile release) of the pharmaceutical composition.

The pharmaceutical preparations can be sterilized and if desired mixedwith auxiliary agents, e.g., lubricants, disintegrants, preservatives,stabilizers, wetting agents, emulsifiers, salts for influencing osmoticpressure buffers, coloring, flavoring and/or aromatic substances and thelike.

The compositions intended for oral use may be prepared according to anymethod known in the art and such compositions may contain one or moreagents selected from the group consisting of inert, non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of the pharmaceutically acceptable dosage forms.

In certain embodiments, the sustained release dosage form may optionallycomprise particles containing an opioid pharmaceutical compositiondescribed above. In certain embodiments, the particles have a diameterfrom about 0.1 mm to about 2.5 mm, preferably from about 0.5 mm to about2 mm. The particles may be film coated with a material that permitsrelease of the active at a sustained rate in an aqueous medium. The filmcoat may be chosen so as to achieve, in combination with the otheringredients of the dosage form, desired release properties. Thesustained release coating formulations of the present invention shouldbe capable of producing a strong, continuous film that is smooth andelegant, capable of supporting pigments and other coating additives,non-toxic, inert, and tack-free.

Coated Beads

In certain embodiments of the present invention a hydrophobic materialis used to coat inert pharmaceutical beads such as nu pariel 18/20beads, and a plurality of the resultant solid sustained release beadsmay thereafter be placed in a gelatin capsule in an amount sufficient toprovide an effective sustained release dose of the opioid pharmaceuticalcomposition when ingested and contacted by an environmental fluid, e.g.,gastric fluid or dissolution media.

The sustained release bead formulations of the present invention slowlyrelease the active of the present invention, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids.

The sustained release profile of the formulations of the invention canbe altered, for example, by varying the amount of overcoating with thehydrophobic material, altering the manner in which a plasticizer isadded to the hydrophobic material, by varying the amount of plasticizerrelative to hydrophobic material, by the inclusion of additionalingredients or excipients, by altering the method of manufacture, etc.

The dissolution profile of the ultimate product may also be modified,for example, by increasing or decreasing the thickness of the retardantcoating.

Spheroids or beads coated with the agent(s) of the present invention areprepared, e.g., by dissolving the pharmaceutical compositions in waterand then spraying the solution onto a substrate, for example, nu pariel18/20 beads, using a Wurster insert. Optionally, additional ingredientsmay be added prior to coating the beads in order to assist the bindingof the pharmaceutical compositions to the beads, and/or to color thesolution, etc. For example, a product which includeshydroxypropylmethylcellulose, etc. with or without colorant (e.g.,Opadry®, commercially available from Colorcon, Inc.) may be added to thesolution and the solution mixed (e.g., for about 1 hour) prior toapplication of the same onto the beads. The resultant coated substrate,in this example beads, may then be optionally overcoated with a barrieragent, to separate the active(s) from the hydrophobic sustained releasecoating. An example of a suitable barrier agent is one which compriseshydroxypropylmethylcellulose. However, any film-former known in the artmay be used. It is preferred that the barrier agent does not affect thedissolution rate of the final product.

The beads may then be overcoated with an aqueous dispersion of thehydrophobic material. The aqueous dispersion of hydrophobic materialpreferably further includes an effective amount of plasticizer, e.g.,triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose,such as Aquacoat® or Surelease®, may be used. If Surelease® is used, itis not necessary to separately add a plasticizer. Alternatively,pre-formulated aqueous dispersions of acrylic polymers such as Eudragit®can be used.

The coating solutions of the present invention preferably contain, inaddition to the film-former, plasticizer, and solvent system (i.e.,water), a colorant to provide elegance and product distinction. Colormay be added to the solution of the therapeutically active agentinstead, or in addition to the aqueous dispersion of hydrophobicmaterial. For example, color may be added to Aquacoat® via the use ofalcohol or propylene glycol based color dispersions, milled aluminumlakes and opacifiers such as titanium dioxide by adding color with shearto water soluble polymer solution and then using low shear to theplasticized Aquacoat®. Alternatively, any suitable method of providingcolor to the formulations of the present invention may be used. Suitableingredients for providing color to the formulation when an aqueousdispersion of an acrylic polymer is used include titanium dioxide andcolor pigments, such as iron oxide pigments. The incorporation ofpigments, may, however, increase the retard effect of the coating.

Plasticized hydrophobic material may be applied onto the substratecomprising the agent(s) by spraying using any suitable spray equipmentknown in the art. In a preferred method, a Wurster fluidized-bed systemis used in which an air jet, injected from underneath, fluidizes thecore material and effects drying while the acrylic polymer coating issprayed on. A sufficient amount of the hydrophobic material to obtain apredetermined sustained release of the pharmaceutical composition whenthe coated substrate is exposed to aqueous solutions, e.g., gastricfluid, may be applied. After coating with the hydrophobic material, afurther overcoat of a film-former, such as, e.g., Opadry®, may beoptionally applied to the beads. This overcoat is provided, if at all,e.g., in order to substantially reduce agglomeration of the beads.

The release of the pharmaceutical composition(s) from the sustainedrelease formulation of the present invention can be further influenced,i.e., adjusted to a desired rate, by the addition of one or morerelease-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic material to water solublematerial is determined by, among other factors, the release raterequired and the solubility characteristics of the materials selected.

The release-modifying agents which function as pore-formers may beorganic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in an environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

The sustained release coatings of the present invention can also includeerosion-promoting agents such as starch and gums.

The sustained release coatings of the present invention can also includematerials useful for making macroporous lamina in the environment ofuse, such as polycarbonates comprised of linear polyesters of carbonicacid in which carbonate groups reoccur in the polymer chain.

The release-modifying agent may also comprise a semi-permeable polymer.

In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

The sustained release coatings of the present invention may also includean exit means comprising at least one passageway, orifice, or the like.The passageway may be formed by such methods as those disclosed in U.S.Pat. Nos. 3,845,770; 3,916,899; 4,063,064; and 4,088,864.

Matrix Formulations

In other embodiments of the present invention, the sustained releaseformulation is achieved via a sustained release matrix optionally havinga sustained release coating as set forth herein. The materials suitablefor inclusion in the sustained release matrix may depend on the methodused to form the matrix.

For example, a matrix in addition to the pharmaceutical compositionsdescribed above may include hydrophilic and/or hydrophobic materials,such as gums, cellulose ethers, acrylic resins, protein derivedmaterials; the list is not meant to be exclusive, and anypharmaceutically acceptable hydrophobic material or hydrophilic materialwhich is capable of imparting sustained release of the pharmaceuticalcomposition(s) and which melts (or softens to the extent necessary to beextruded) may be used in accordance with the present invention.

The oral dosage form may contain between 1% and 80% (by weight) of oneor more hydrophilic or hydrophobic material(s).

The hydrophobic material is preferably selected from the groupconsisting of alkylcelluloses, acrylic and methacrylic acid polymers andcopolymers, shellac, zein, hydrogenated castor oil, hydrogenatedvegetable oil, or mixtures thereof. In certain preferred embodiments ofthe present invention, the hydrophobic material is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid)(anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. In other embodiments, the hydrophobicmaterial is selected from materials such as hydroxyalkylcelluloses suchas hydroxypropylmethylcellulose and mixtures of the foregoing. Of thesematerials, acrylic polymers, e.g., Eudragit® RSPO, the cellulose ethers,e.g., hydroxyalkylcelluloses and carboxyalkylcelluloses are preferred.

Preferred hydrophobic materials are water-insoluble with more or lesspronounced hydrophilic and/or hydrophobic trends. Preferably, thehydrophobic materials useful in the invention have a melting point fromabout 40° C. to about 200° C., preferably from about 45° C. to about 90°C. Specifically, the hydrophobic material may comprise natural orsynthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl,cetyl or preferably cetostearyl alcohol), fatty acids, including but notlimited to fatty acid esters, fatty acid glycerides (mono-, di-, andtri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearicacid, stearyl alcohol and hydrophobic and hydrophilic materials havinghydrocarbon backbones. Suitable waxes are waxes as defined in Fette,Seifen, Anstrichmittel 76, 135 (1974) and include, for example, beeswax,glycowax, castor wax and carnauba wax.

Suitable hydrophobic materials which may be used in accordance with thepresent invention include long chain (C₈-C₅₀, especially C₁₂-C₄₀),substituted or unsubstituted hydrocarbons, such as fatty acids, fattyalcohols, glyceryl esters of fatty acids, mineral and vegetable oils andnatural and synthetic waxes. Hydrocarbons having a melting point ofbetween 25° C. and 90° C. are preferred. Of the long chain hydrocarbonmaterials, fatty (aliphatic) alcohols are preferred in certainembodiments. The oral dosage form may contain up to 60% of at least onelong chain hydrocarbon.

In certain embodiments, a combination of two or more hydrophobicmaterials is included in the matrix formulations. If an additionalhydrophobic material is included, it is preferably selected from naturaland synthetic waxes, fatty acids, fatty alcohols, and mixtures of thesame. Examples include beeswax, carnauba wax, stearic acid and stearylalcohol. This list is not meant to be exclusive.

One particular suitable matrix comprises at least one water solublehydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferably C₁₄-C₂₂,aliphatic alcohol and, optionally, at least one polyalkylene glycol. Theat least one hydroxyalkyl cellulose is preferably a hydroxy (C₁ to C₆)alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethylcellulose. Theamount of the at least one hydroxyalkyl cellulose in the present oraldosage form will be determined, inter alia, by the precise rate of APIrelease required. The at least one aliphatic alcohol may be, forexample, lauryl alcohol, myristyl alcohol or stearyl alcohol. Inparticularly preferred embodiments of the present oral dosage form,however, the at least one aliphatic alcohol is cetyl alcohol orcetostearyl alcohol. The amount of the at least one aliphatic alcohol inthe present oral dosage form will be determined, as above, by theprecise rate of opioid release required. It will also depend on whetherat least one polyalkylene glycol is present in or absent from the oraldosage form. In the absence of at least one polyalkylene glycol, theoral dosage form preferably contains between 20% and 50% (by weight) ofthe at least one aliphatic alcohol. When at least one polyalkyleneglycol is present in the oral dosage form, then the combined weight ofthe at least one aliphatic alcohol and the at least one polyalkyleneglycol preferably constitutes between 20% and 50% (by weight) of thetotal dosage.

In one embodiment, the ratio of, e.g., the at least one hydroxyalkylcellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a (w/w) of the at least onehydroxyalkyl cellulose to the at least one aliphaticalcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with aratio of between 1:3 and 1:4 being particularly preferred.

In certain embodiments, the oral dosage form contains at least onepolyalkylene glycol. The amount of the at least one polyalkylene glycolin the oral dosage form may be up to 60%. The at least one polyalkyleneglycol may be, for example, polypropylene glycol or, which is preferred,polyethylene glycol. The number average molecular weight of the at leastone polyalkylene glycol is preferred between 1,000 and 15,000 especiallybetween 1,500 and 12,000.

In certain embodiments, the sustained release matrix may comprisepolyethylene oxide. In certain embodiments polyethylene oxide comprisesfrom about 40% to about 95% of the dosage form. In certain embodimentspolyethylene oxide comprises from about 50% to about 95% of the dosageform. In certain embodiments polyethylene oxide comprises from about 55%to about 90% of the dosage form. In certain embodiments polyethyleneoxide comprises from about 60% to about 90% of the dosage form.

Another suitable sustained release matrix would comprise analkylcellulose (especially ethyl cellulose), a C₁₂ to C₃₆ aliphaticalcohol and, optionally, a polyalkylene glycol.

In another preferred embodiment, the matrix includes a pharmaceuticallyacceptable combination of at least two hydrophobic materials.

In addition to the above ingredients, a sustained release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

Matrix-Particulates

In order to facilitate the preparation of a solid, sustained release,oral dosage form according to this invention, any method of preparing amatrix formulation known to those skilled in the art may be used. Forexample incorporation in the matrix may be effected, for example, by (a)forming granules comprising at least one water soluble hydroxyalkylcellulose, and an opioid according to present invention; (b) mixing thehydroxyalkyl cellulose containing granules with at least one C₁₂-C₃₆aliphatic alcohol; and (c) optionally, compressing and shaping thegranules. Preferably, the granules are formed by wet granulating thehydroxyalkyl cellulose granules with water.

In yet other alternative embodiments, a spheronizing agent, togetherwith the active can be spheronized to form spheroids. Microcrystallinecellulose is a preferred spheronizing agent. A suitable microcrystallinecellulose is, for example, the material sold as Avicel PH 101 (TradeMark, FMC Corporation). In such embodiments, in addition to the activeingredient and spheronizing agent, the spheroids may also contain abinder. Suitable binders, such as low viscosity, water soluble polymers,will be well known to those skilled in the pharmaceutical art. However,water soluble hydroxy lower alkyl cellulose, such ashydroxypropylcellulose, is preferred. Additionally (or alternatively)the spheroids may contain a water insoluble polymer, especially anacrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethylacrylate copolymer, or ethyl cellulose. In such embodiments, thesustained release coating will generally include a hydrophobic materialsuch as (a) a wax, either alone or in admixture with a fatty alcohol; or(b) shellac or zein.

Melt Extrusion Matrix

Sustained release matrices can also be prepared via melt-granulation ormelt-extrusion techniques. Generally, melt-granulation techniquesinvolve melting a normally solid hydrophobic material, e.g., a wax, andincorporating a powdered drug therein. To obtain a sustained releasedosage form, it may be necessary to incorporate an additionalhydrophobic substance, e.g., ethylcellulose or a water-insoluble acrylicpolymer, into the molten wax hydrophobic material. Examples of sustainedrelease formulations prepared via melt-granulation techniques are foundin U.S. Pat. No. 4,861,598.

The additional hydrophobic material may comprise one or morewater-insoluble wax-like thermoplastic substances possibly mixed withone or more wax-like thermoplastic substances being less hydrophobicthan said one or more water-insoluble wax-like substances. In order toachieve constant release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like substances may be those with a water-solubilitythat is lower than about 1:5,000 (w/w). For purposes of the presentinvention, a wax-like substance is defined as any material which isnormally solid at room temperature and has a melting point of from about25° to about 100° C.

In addition to the above ingredients, a sustained release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art. The quantitiesof these additional materials will be sufficient to provide the desiredeffect to the desired formulation.

In addition to the above ingredients, a sustained release matrixincorporating melt-extruded multiparticulates may also contain suitablequantities of other materials, e.g., diluents, lubricants, binders,granulating aids, colorants, flavorants and glidants that areconventional in the pharmaceutical art in amounts up to about 50% of theparticulate if desired.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986).

Melt Extrusion Multiparticulates

The preparation of a suitable melt-extruded matrix according to thepresent invention may, for example, include the steps of blending theAPI together with at least one hydrophobic material and preferably theadditional hydrophobic material to obtain a homogeneous mixture. Thehomogeneous mixture is then heated to a temperature sufficient to atleast soften the mixture sufficiently to extrude the same. The resultinghomogeneous mixture is then extruded to form strands. The extrudate ispreferably cooled and cut into multiparticulates by any means known inthe art. The strands are cooled and cut into multiparticulates. Themultiparticulates are then divided into unit doses. The extrudatepreferably has a diameter of from about 0.1 to about 5 mm and providessustained release of the API for a time period of from about 8 to about24 hours.

An optional process for preparing the melt extrusions of the presentinvention includes directly metering into an extruder a hydrophobicmaterial, the opioid API, and an optional binder; heating the homogenousmixture; extruding the homogenous mixture to thereby form strands;cooling the strands containing the homogeneous mixture; cutting thestrands into particles having a size from about 0.1 mm to about 12 mm;and dividing said particles into unit doses. In this aspect of theinvention, a relatively continuous manufacturing procedure is realized.

The diameter of the extruder aperture or exit port can also be adjustedto vary the thickness of the extruded strands. Furthermore, the exitpart of the extruder need not be round; it can be oblong, rectangular,etc. The exiting strands can be reduced to particles using a hot wirecutter, guillotine, etc.

The melt extruded multiparticulate system can be, for example, in theform of granules, spheroids or pellets depending upon the extruder exitorifice. For purposes of the present invention, the terms “melt-extrudedmultiparticulate(s)” and “melt-extruded multiparticulate system(s)” and“melt-extruded particles” shall refer to a plurality of units,preferably within a range of similar size and/or shape and containingone or more active agents and one or more excipients, preferablyincluding a hydrophobic material as described herein. In this regard,the melt-extruded multiparticulates will be of a range of from about 0.1to about 12 mm in length and have a diameter of from about 0.1 to about5 mm. In addition, it is to be understood that the melt-extrudedmultiparticulates can be any geometrical shape within this size range.Alternatively, the extrudate may simply be cut into desired lengths anddivided into unit doses of the therapeutically active agent without theneed of a spheronization step.

In one preferred embodiment, oral dosage forms are prepared to includean effective amount of melt-extruded multiparticulates within a capsule.For example, a plurality of the melt-extruded multiparticulates may beplaced in a gelatin capsule in an amount sufficient to provide aneffective sustained release dose when ingested and contacted by gastricfluid.

In another preferred embodiment, a suitable amount of themultiparticulate extrudate is compressed into an oral tablet usingconventional tableting equipment using standard techniques. Techniquesand compositions for making tablets (compressed and molded), capsules(hard and soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980).

In yet another preferred embodiment, the extrudate can be shaped intotablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et. al.),described in additional detail above.

Optionally, the sustained release melt-extruded multiparticulate systemsor tablets can be coated, or the gelatin capsule containing themultiparticulates can be further coated, with a sustained releasecoating such as the sustained release coatings described above. Suchcoatings preferably include a sufficient amount of hydrophobic materialto obtain a weight gain level from about 2 to about 30 percent, althoughthe overcoat may be greater depending upon the desired release rate,among other things.

The melt-extruded unit dosage forms of the present invention may furtherinclude combinations of melt-extruded particles before beingencapsulated. Furthermore, the unit dosage forms can also include anamount of an immediate release agent for prompt release. The immediaterelease agent may be incorporated, e.g., as separate pellets within agelatin capsule, or may be coated on the surface of themultiparticulates after preparation of the dosage forms (e.g., sustainedrelease coating or matrix-based). The unit dosage forms of the presentinvention may also contain a combination of sustained release beads andmatrix multiparticulates to achieve a desired effect.

The sustained release formulations of the present invention preferablyslowly release the agent(s), e.g., when ingested and exposed to gastricfluids, and then to intestinal fluids. The sustained release profile ofthe melt-extruded formulations of the invention can be altered, forexample, by varying the amount of retardant, i.e., hydrophobic material,by varying the amount of plasticizer relative to hydrophobic material,by the inclusion of additional ingredients or excipients, by alteringthe method of manufacture, etc.

In other embodiments of the invention, the melt extruded material isprepared without the inclusion of the API, which can be added thereafterto the extrudate. Such formulations typically will have the agentsblended together with the extruded matrix material, and then the mixturewould be tableted in order to provide a slow release formulation.

Coatings

The dosage forms of the present invention may optionally be coated withone or more materials suitable for the regulation of release or for theprotection of the formulation. In one embodiment, coatings are providedto permit either pH-dependent or pH-independent release. A pH-dependentcoating serves to release the active in desired areas of thegastro-intestinal (GI) tract, e.g., the stomach or small intestine, suchthat an absorption profile is provided which is capable of providing atleast about eight hours and preferably about twelve hours to up to abouttwenty-four hours of the therapeutic effect (such as analgesia) to apatient. When a pH-independent coating is desired, the coating isdesigned to achieve optimal release regardless of pH-changes in theenvironmental fluid, e.g., the GI tract. It is also possible toformulate compositions which release a portion of the dose in onedesired area of the GI tract, e.g., the stomach, and release theremainder of the dose in another area of the GI tract, e.g., the smallintestine.

Formulations according to the invention that utilize pH-dependentcoatings to obtain formulations may also impart a repeat-action effectwhereby unprotected drug is coated over the enteric coat and is releasedin the stomach, while the remainder, being protected by the entericcoating, is released further down the gastrointestinal tract. Coatingswhich are pH-dependent may be used in accordance with the presentinvention include shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, andmethacrylic acid ester copolymers, zein, and the like.

In certain preferred embodiments, the substrate (e.g., tablet core bead,matrix particle) containing the API is coated with a hydrophobicmaterial selected from (i) an alkylcellulose; (ii) an acrylic polymer;or (iii) mixtures thereof. The coating may be applied in the form of anorganic or aqueous solution or dispersion. The coating may be applied toobtain a weight gain from about 2 to about 25% of the substrate in orderto obtain a desired sustained release profile. Coatings derived fromaqueous dispersions are described, e.g., in detail in U.S. Pat. Nos.5,273,760 and 5,286,493.

Other examples of sustained release formulations and coatings which maybe used in accordance with the present invention include those describedin U.S. Pat. Nos. 5,324,351; 5,356,467, and 5,472,712.

Alkylcellulose Polymers

Cellulosic materials and polymers, including alkylcelluloses, providehydrophobic materials well suited for coating the beads according to theinvention. Simply by way of example, one preferred alkylcellulosicpolymer is ethylcellulose, although the artisan will appreciate thatother cellulose and/or alkylcellulose polymers may be readily employed,singly or in any combination, as all or part of a hydrophobic coatingaccording to the invention.

Acrylic Polymers

In other preferred embodiments of the present invention, the hydrophobicmaterial comprising the sustained release coating is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate copolymers,ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamide copolymer,poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate)copolymer, polyacrylamide, aminoalkyl methacrylate copolymer,poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers. Ammonio methacrylatecopolymers are well known in the art, and are described in NF XVII asfully polymerized copolymers of acrylic and methacrylic acid esters witha low content of quaternary ammonium groups.

In order to obtain a desirable dissolution profile, it may be necessaryto incorporate two or more ammonio methacrylate copolymers havingdiffering physical properties, such as different molar ratios of thequaternary ammonium groups to the neutral (meth)acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparingpH-dependent coatings which may be used in accordance with the presentinvention. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit® from Evonik. Thereare several different types of Eudragit®. For example, Eudragit® E is anexample of a methacrylic acid copolymer which swells and dissolves inacidic media. Eudragit® L is a methacrylic acid copolymer which does notswell at about pH<5.7 and is soluble at about pH>6. Eudragit® S does notswell at about pH<6.5 and is soluble at about pH>7. Eudragit® RL andEudragit® RS are water swellable, and the amount of water absorbed bythese polymers is pH-dependent, however, dosage forms coated withEudragit® RL and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from Evonikunder the trade names Eudragit® RL30D and Eudragit® RS30D, respectively.Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic andmethacrylic esters with a low content of quaternary ammonium groups, themolar ratio of ammonium groups to the remaining neutral (meth)acrylicesters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D. Themean molecular weight is about 150,000. The code designations RL (highpermeability) and RS (low permeability) refer to the permeabilityproperties of these agents. Eudragit® RL/RS mixtures are insoluble inwater and in digestive fluids. However, coatings formed from the sameare swellable and permeable in aqueous solutions and digestive fluids.

The Eudragit® RL/RS dispersions may be mixed together in any desiredratio in order to ultimately obtain a sustained release formulationhaving a desirable dissolution profile. Desirable sustained releaseformulations may be obtained, for instance, from a retardant coatingderived from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS,and 10% Eudragit® RL and 90% Eudragit® RS. Of course, one skilled in theart will recognize that other acrylic polymers may also be used, suchas, for example, Eudragit® L.

Plasticizers

In embodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic material, the inclusion of aneffective amount of a plasticizer in the aqueous dispersion ofhydrophobic material will further improve the physical properties of thesustained release coating. For example, because ethyl-cellulose has arelatively high glass transition temperature and does not form flexiblefilms under normal coating conditions, it is preferable to incorporate aplasticizer into an ethylcellulose coating containing sustained releasecoating before using the same as a coating material. Generally, theamount of plasticizer included in a coating solution is based on theconcentration of the film-former, e.g., most often from about 1 to about50 percent of the film-former. Concentration of the plasticizer,however, can only be properly determined after careful experimentationwith the particular coating solution and method of application.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tributyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is an especially preferred plasticizer for the aqueousdispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

It has further been found that the addition of a small amount of talcreduces the tendency of the aqueous dispersion to stick duringprocessing, and acts as a polishing agent.

Sustained Release Osmotic Dosage Form

Sustained release dosage forms according to the present invention mayalso be prepared as osmotic dosage formulations. The osmotic dosageforms preferably include a bilayer core comprising a drug layer (e.g.,containing oxymorphone or a salt or solvate thereof as described above)and a delivery or push layer, wherein the bilayer core is surrounded bya semipermeable wall and optionally having at least one passagewaydisposed therein.

The expression “passageway” as used for the purpose of the presentdescription, includes aperture, orifice, bore, pore, porous elementthrough which an API (e.g., oxymorphone hydrochloride) may be pumped,diffuse or migrate through a fiber, capillary tube, porous overlay,porous insert, microporous member, or porous composition. The passagewaycan also include a compound that erodes or is leached from the wall inthe fluid environment of use to produce at least one passageway.Representative compounds for forming a passageway include erodiblepoly(glycolic) acid, or poly(lactic) acid in the wall; a gelatinousfilament; a water-removable poly(vinyl alcohol); leachable compoundssuch as fluid-removable pore-forming polysaccharides, acids, salts oroxides. A passageway can be formed by leaching a compound from the wall,such as sorbitol, sucrose, lactose, maltose, or fructose, to form asustained-release dimensional pore-passageway. The dosage form can bemanufactured with one or more passageways in spaced-apart relation onone or more surfaces of the dosage form. A passageway and equipment forforming a passageway are disclosed in U.S. Pat. Nos. 3,845,770;3,916,899; 4,063,064 and 4,088,864. Passageways comprisingsustained-release dimensions sized, shaped and adapted as areleasing-pore formed by aqueous leaching to provide a releasing-pore ofa sustained-release rate are disclosed in U.S. Pat. Nos. 4,200,098 and4,285,987.

In certain embodiments the drug layer may also comprise at least onepolymer hydrogel. The polymer hydrogel may have an average molecularweight of between about 500 and about 6,000,000. Examples of polymerhydrogels include but are not limited to a maltodextrin polymercomprising the formula (C₆H₁₂O₅)_(n)H₂O, wherein n is 3 to 7,500, andthe maltodextrin polymer comprises a 500 to 1,250,000 number-averagemolecular weight; a poly(alkylene oxide) represented by, e.g., apoly(ethylene oxide) and a poly(propylene oxide) having a 50,000 to750,000 weight-average molecular weight, and more specificallyrepresented by a poly(ethylene oxide) of at least one of 100,000,200,000, 300,000 or 400,000 weight-average molecular weights; an alkalicarboxyalkylcellulose, wherein the alkali is sodium or potassium, thealkyl is methyl, ethyl, propyl, or butyl of 10,000 to 175,000weight-average molecular weight; and a copolymer of ethylene-acrylicacid, including methacrylic and ethacrylic acid of 10,000 to 500,000number-average molecular weight.

In certain embodiments of the present invention, the delivery or pushlayer comprises an osmopolymer. Examples of the osmopolymer include butare not limited to a member selected from the group consisting of apolyalkylene oxide and a carboxyalkylcellulose. The polyalkylene oxidepossesses a 1,000,000 to Ser. No. 10/000,000 weight-average molecularweight. The polyalkylene oxide may be a member selected from the groupconsisting of polymethylene oxide, polyethylene oxide, polypropyleneoxide, polyethylene oxide having a 1,000,000 average molecular weight,polyethylene oxide comprising a 5,000,000 average molecular weight,polyethylene oxide comprising a 7,000,000 average molecular weight,cross-linked polymethylene oxide possessing a 1,000,000 averagemolecular weight, and polypropylene oxide of 1,200,000 average molecularweight. Typical osmopolymer carboxyalkylcellulose comprises a memberselected from the group consisting of alkali carboxyalkylcellulose,sodium carboxymethylcellulose, potassium carboxymethylcellulose, sodiumcarboxyethylcellulose, lithium carboxymethylcellulose, sodiumcarboxyethylcellulose, carboxyalkylhydroxyalkylcellulose,carboxymethylhydroxyethyl cellulose, carboxyethylhydroxyethylcelluloseand carboxymethylhydroxypropylcellulose. The osmopolymers used for thedisplacement layer exhibit an osmotic pressure gradient across thesemipermeable wall. The osmopolymers imbibe fluid into dosage form,thereby swelling and expanding as an osmotic hydrogel (also known asosmogel), whereby they push the active pharmaceutical ingredient (e.g.,oxymorphone hydrochloride) from the osmotic dosage form.

The push layer may also include one or more osmotically effectivecompounds also known as osmagents and as osmotically effective solutes.They imbibe an environmental fluid, for example, from thegastrointestinal tract, into dosage form and contribute to the deliverykinetics of the displacement layer. Examples of osmotically activecompounds comprise a member selected from the group consisting ofosmotic salts and osmotic carbohydrates. Examples of specific osmagentsinclude but are not limited to sodium chloride, potassium chloride,magnesium sulfate, lithium phosphate, lithium chloride, sodiumphosphate, potassium sulfate, sodium sulfate, potassium phosphate,glucose, fructose and maltose.

The push layer may optionally include a hydroxypropylalkylcellulosepossessing a 9,000 to 450,000 number-average molecular weight. Thehydroxypropylalkylcellulose is represented by a member selected from thegroup consisting of hydroxypropylmethylcellulose,hydroxypropylethylcellulose, hydroxypropyl isopropyl cellulose,hydroxypropylbutylcellulose, and hydroxypropylpentylcellulose.

The push layer optionally may comprise a nontoxic colorant or dye.Examples of colorants or dyes include but are not limited to Food andDrug Administration Colorant (FD&C), such as FD&C No. 1 blue dye, FD&CNo. 4 red dye, red ferric oxide, yellow ferric oxide, titanium dioxide,carbon black, and indigo.

The push layer may also optionally comprise an antioxidant to inhibitthe oxidation of ingredients. Some examples of antioxidants include butare not limited to a member selected from the group consisting ofascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixtureof 2 and 3 tert-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodiumisoascorbate, dihydroguaretic acid, potassium sorbate, sodium bisulfate,sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E,4-chloro-2,6-di-tert butylphenol, a-tocopherol, and propylgallate.

In certain alternative embodiments, the dosage form comprises ahomogenous core comprising an active pharmaceutical ingredient (e.g.,oxymorphone hydrochloride), a pharmaceutically acceptable polymer (e.g.,polyethylene oxide), optionally a disintegrant (e.g.,polyvinylpyrrolidone), optionally an absorption enhancer (e.g., a fattyacid, a surfactant, a chelating agent, a bile salt, etc.). Thehomogenous core is surrounded by a semipermeable wall having apassageway (as defined above) for the release of the opioid API.

In certain embodiments, the semipermeable wall comprises a memberselected from the group consisting of a cellulose ester polymer, acellulose ether polymer and a cellulose ester-ether polymer.Representative wall polymers comprise a member selected from the groupconsisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di- and tricellulose alkenylates, and mono-, di- andtricellulose alkinylates. The poly(cellulose) used for the presentinvention comprises a number-average molecular weight of 20,000 to7,500,000.

Additional semipermeable polymers for the purpose of this inventioncomprise acetaldehyde dimethycellulose acetate, cellulose acetateethylcarbamate, cellulose acetate methylcarbamate, cellulose diacetate,propylcarbamate, cellulose acetate diethylaminoacetate; semipermeablepolyamide; semipermeable polyurethane; semipermeable sulfonatedpolystyrene; semipermeable cross-linked polymer formed by thecoprecipitation of a polyanion and a polycation as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,876;semipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Pat.No. 3,133,132; semipermeable crosslinked polystyrenes; semipermeablecross-linked poly(sodium styrene sulfonate); semipermeable crosslinkedpoly(vinylbenzyltrimethyl ammonium chloride); and semipermeable polymerspossessing a fluid permeability of 2.5×1⁸ to 2.5×10⁻² (cm²/hr atm)expressed per atmosphere of hydrostatic or osmotic pressure differenceacross the semipermeable wall. Other polymers useful in the presentinvention are known in the art in U.S. Pat. Nos. 3,845,770; 3,916,899and 4,160,020; and in Handbook of Common Polymers, Scott, J. R. and W.J. Roff, 1971, CRC Press, Cleveland, Ohio.

In certain embodiments, preferably the semipermeable wall is nontoxic,inert, and it maintains its physical and chemical integrity during thedispensing life of the drug. In certain embodiments, the dosage formcomprises a binder. An example of a binder includes, but is not limitedto a therapeutically acceptable vinyl polymer having a 5,000 to 350,000viscosity-average molecular weight, represented by a member selectedfrom the group consisting of poly-n-vinylamide, poly-n-vinylacetamide,poly(vinyl pyrrolidone), also known as poly-n-vinylpyrrolidone,poly-n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, andpoly-n-vinyl-pyrrolidone copolymers with a member selected from thegroup consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinylfluoride, vinyl butyrate, vinyl laureate, and vinyl stearate. Otherbinders include for example, acacia, starch, gelatin, andhydroxypropylalkylcellulose of from 9,200 to 250,000 average molecularweight.

In certain embodiments, the dosage form comprises a lubricant, which maybe used during the manufacture of the dosage form to prevent sticking todie wall or punch faces. Examples of lubricants include but are notlimited to magnesium stearate, sodium stearate, stearic acid, calciumstearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid,sodium stearyl fumarate, and magnesium palmitate.

Suppositories

The sustained release formulations of the present invention may beformulated as a pharmaceutical suppository for rectal administrationcomprising a suitable suppository base, and a pharmaceutical opioidcomposition. Preparation of sustained release suppository formulationsis described in, e.g., U.S. Pat. No. 5,215,758.

Prior to absorption, the drug must be in solution. In the case ofsuppositories, solution must be preceded by dissolution of thesuppository base, or the melting of the base and subsequent partition ofthe drug from the suppository base into the rectal fluid. The absorptionof the drug into the body may be altered by the suppository base. Thus,the particular suppository base to be used in conjunction with aparticular drug must be chosen giving consideration to the physicalproperties of the drug. For example, lipid-soluble drugs will notpartition readily into the rectal fluid, but drugs that are onlyslightly soluble in the lipid base will partition readily into therectal fluid.

Among the different factors affecting the dissolution time (or releaserate) of the drugs are the surface area of the drug substance presentedto the dissolution solvent medium, the pH of the solution, thesolubility of the substance in the specific solvent medium, and thedriving forces of the saturation concentration of dissolved materials inthe solvent medium. Generally, factors affecting the absorption of drugsfrom suppositories administered rectally include suppository vehicle,absorption site pH, drug pKa, degree of ionization, and lipidsolubility.

The suppository base chosen should be compatible with the active of thepresent invention. Further, the suppository base is preferably non-toxicand nonirritating to mucous membranes, melts or dissolves in rectalfluids, and is stable during storage.

In certain preferred embodiments of the present invention for bothwater-soluble and water-insoluble drugs, the suppository base comprisesa fatty acid wax selected from the group consisting of mono-, di- andtriglycerides of saturated, natural fatty acids of the chain length C₁₂to C₁₈.

In preparing the suppositories of the present invention other excipientsmay be used. For example, a wax may be used to form the proper shape foradministration via the rectal route. This system can also be usedwithout wax, but with the addition of diluent filled in a gelatincapsule for both rectal and oral administration.

Examples of suitable commercially available mono-, di- and triglyceridesinclude saturated natural fatty acids of the 12-18 carbon atom chainsold under the trade name Novata™ (types AB, AB, B, BC, BD, BBC, E, BCF,C, D and 299), manufactured by Henkel, and Witepsol™ (types H5, H12,H15, H175, H185, H19, H32, H35, H39, H42, W25, W31, W35, W45, S55, S58,E75, E76 and E85), manufactured by Dynamit Nobel.

Other pharmaceutically acceptable suppository bases may be substitutedin whole or in part for the above-mentioned mono-, di- andtriglycerides. The amount of base in the suppository is determined bythe size (i.e. actual weight) of the dosage form, the amount of base(e.g., alginate) and drug used. Generally, the amount of suppositorybase is from about 20 percent to about 90 percent of the total weight ofthe suppository. Preferably, the amount of suppository base in thesuppository is from about 65 percent to about 80 percent, of the totalweight of the suppository.

The following examples are meant to illustrate, but in no way to limit,the present invention.

EXAMPLES Comparative Example 1

Preparation of oxymorphone according to Example 2 of WO 2008/130553

Example 2 from WO 2008/130553 was repeated as follows.

1. Into a 100 mL reaction vessel equipped with a temperature probe, anoverhead stirrer and a reflux condenser, oripavine (3.03 g, 10.2 mmol)was charged as a slurry in deionized water (9 mL).

2. The reaction mixture was stirred at 300 rpm, while maintaining aninternal temperature of 20° C.

3. Formic acid (88%, 6 mL, 139.9 mmol) was added into the reactionmixture. Upon the addition, the solids readily dissolved into solution.During the formic acid addition, the temperature of the reaction mixtureincreased to 30° C.

4. After the solution temperature had cooled to 20° C., 35% hydrogenperoxide (1.06 mL, 15.8 mmol) and sulfuric acid (0.45 mL, 8.15 mmol)were added to the reaction.

5. The reaction was stirred (300 rpm) at 20° C. for 16 hours, untilabout 95% of the oripavine had been consumed according to the HPLCanalysis described in Example 12.

6. 0.30 g of 5% palladium on carbon was charged into the reactionmixture, and the mixture was stirred at 20° C. for 30 minutes.

7. Sodium formate (0.60 g, 8.82 mmol) and triethylamine (7.5 mL, 53.8mmol) were added to the reaction mixture, and the mixture was heated to45° C. and stirred at 45° C. for 2 hours.

8. The mixture was heated to 80° C. and stirred at 80° C. for anadditional 8 hours.

9. The reaction was then cooled to 20° C. and stirred at 20° C. for 8hours. No precipitation was observed at this temperature.

10. The reaction mixture was filtered through a plug of celite.

11. The filtrate was basified to a pH of about 9.3 with concentratedammonium hydroxide, to precipitate oxymorphone free base.

12. The resulting mixture was stirred at room temperature for 1 hour.

13. The resulting mixture was then filtered, washed with water (3×15mL), and dried in a vacuum oven at 80° C. for 16 hours to yield 2.04 gof solid.

14. Analysis of the solid by the HPLC method of Example 12 showed anHPLC peak area ratio ofoxymorphone:14-hydroxymorphinone:8-hydroxyoxymorphone of Ser. No.15/803,069:1,845:25,714. The oxymorphone base comprised 96.03% of thecomposition (based on HPLC area percent), 14-hydroxymorphinone comprised117 ppm of the composition (based on HPLC area percent), and8-hydroxyoxymorphone comprised 1627 ppm of the composition (based onHPLC area percent). The auto-scaled chromatogram and peak results fromthis analysis are depicted in FIG. 1.

About 14.5 molar equivalents of total acid per molar equivalent oforipavine were used in this example (13.7 molar equivalents of HCO₂H,0.81 molar equivalents of H₂SO₄). The molar ratio of sulfuric acid toformic acid was about 1:16,9. No precipitation was observed up to step11.

Comparative Example 2 Preparation of Oxymorphone Free Base according toExample 3 of WO 2008/130553

Example 3 from WO 2008/130553 was repeated as follows.

1. Into a 100 mL reaction vessel equipped with a temperature probe,overhead stirrer and reflux condenser, oripavine (3.01 g, 10.1 mmol) wascharged as a slurry in deionized water (9 mL).

2. The reaction mixture was stirred at 300 rpm, while maintaining aninternal temperature of 20° C.

3. Formic acid (88%, 6 mL, 139.9 mmol) was added into the reaction. Uponthe addition, the solids readily dissolved into solution. During theformic acid addition, the temperature of the reaction mixture increasedto 30° C.

4. After the solution temperature had cooled to 20° C., 35% hydrogenperoxide (1.06 mL, 15.8 mmol) and sulfuric acid (0.45 mL, 8.15 mmol)were added to the reaction.

5. The reaction was stirred (300 rpm) at 20° C. for 16 hours, until theoripavine had been consumed according to the HPLC analysis of Example12.

6. 0.30 g of 5% palladium on carbon was charged into the reactionmixture, and the mixture was stirred at 20° C. for 30 minutes.

7. Triethylamine (8.8 mL, 63.1 mmol) was added to the reaction mixture,and the reaction mixture was heated to 45° C. and stirred at 45° C. for2 hours.

8. The mixture was heated to 80° C. and stirred at 80° C. for anadditional 8 hours.

9. The reaction was then cooled to 20° C. and stirred at 20° C. for 8hours. No solid precipitation was observed at this temperature.

10. The reaction mixture was filtered through a plug of celite.

11. The filtrate was basified to pH=9.25 with concentrated ammoniumhydroxide, and the precipitated composition was allowed to stir at roomtemperature for 1 hour.

12. The precipitated composition was then filtered, washed with water(3×15 mL) and dried in a vacuum oven at 80° C. for 16 hours to yield1.33 g of precipitate.

13. Analysis of the precipitate by the HPLC method of Example 12 showedan HPLC peak area ratio ofoxymorphone:14-hydroxymorphinone:8-hydroxyoxymorphone of Ser. No.13/906,304:2,146:46,937. In other words, the oxymorphone base comprised94.94% of the composition (based on HPLC area percent),14-hydroxymorphinone comprised 154 ppm of the composition (based on HPLCarea percent), and 8-hydroxyoxymorphone comprised 3377 ppm of thecomposition (based on HPLC area percent). The auto-scaled chromatogramand peak results from this analysis are depicted in FIG. 2.

About 14.7 molar equivalents of total acid per molar equivalent oforipavine were used in this example. The molar ratio of sulfuric acid toformic acid was about 1:17,2. No precipitation was observed up to step11.

Example 3 Preparation of 14-Hydroxymorphinone from Oripavine withoutSulfuric Acid

1. Oripavine (99.99 g, 336 mmol) was charged as a slurry in deionizedwater (150 mL) into a 500 mL jacketed vessel.

2. The slurry was stirred (250 rpm) at ambient reaction temperature(approximately 25° C.).

3. Formic acid (100 mL, 2332 mmol, 88%) was added to the mixture in oneportion. The solids completely dissolved upon the addition, and a slightexothermic reaction was observed (temperature increase to approximately34° C.). The solution was then allowed to cool back to ambienttemperature (approximately 25° C.).

4. While holding the temperature at approximately 25° C., hydrogenperoxide (31.2 mL, 363 mmol, 35%, M=11.86) was added to the solution ata controlled rate of 1.56 mL/minute (0.05 equivalents/minute).

5. After addition was complete, the solution was allowed to stir anadditional 30 minutes at ambient temperature.

6. The solution was then heated to 48° C. and held at this temperaturefor about 3.5 hours, and sampled by HPLC for reaction completion.

7. After approximately 3.5 hours of stirring at 48° C., the solution wascooled to 10° C. over 35 minutes.

8. The solution was held at 10° C. for approximately 16 hours, andanalyzed by HPLC. A sample was shown to contain 97.04% (based on HPLCarea percent) 14-hydroxymorphinone, 5200 ppm (based on HPLC areapercent) oripavine, and 10900 ppm (based on HPLC area percent)8-hydroxyoxymorphone.

9. The solution was then utilized for subsequent hydrogenation inExample 4.

Example 4 Preparation of Oxymorphone from 14-Hydroxymorphinone

1. 5% Palladium on carbon (0.60 g) was charged into a 1 L ZipperClave®autoclave high pressure reaction vessel, followed by the solutionprepared in Example 3.

2. Deionized water (100 mL) and formic acid (100 mL, 88%, 2332 mmol)were added into the reaction solution in one portion.

3. The vessel was sealed and hydrogenated at 60 psia (413.69 kPa), 55°C., for 3 hours and 10 minutes.

4. The solution was vented and purged with nitrogen 3 times.

5. A sample of the solution was analyzed by HPLC for reactioncompletion.

6. The palladium on carbon was removed from the solution by filtrationthrough 2 layers of filter paper and the filtrate was stored in arefrigerator at approximately 5° C. overnight.

7. The filtrate was transferred to a cooled 1 L jacketed vessel (O-5°C.).

8. 50% sodium hydroxide was added into the cooled solution at a ratesuch that the temperature of the solution did not exceed 20° C., until afinal pH in a range from 9.0 to 9.25 was achieved.

9. The resulting solids were stirred at 5° C. for an additional 30minutes before being filtered by vacuum filtration through a paperfilter (Whatman#2).

10. The resulting solid material was slurry washed with deionized water(3×200 mL) and further dried by vacuum on the filter for 1 hour, beforebeing transferred to a vacuum oven and dried at 40° C. under housevacuum (˜28 mmHg (3.73 kPa)). The solid material was analyzed by HPLC.The analysis showed that the solid material contained 95.96%oxymorphone, based on HPLC area percent, 3100 ppm 14-hydroxymorphinone,based on HPLC area percent, and 19600 ppm 8-hydroxyoxymorphone, based onHPLC area percent.

About 6.94 molar equivalents of formic acid per molar equivalent oforipavine were used in example 3, i.e. during the oxidation. No sulfuricacid was used. No precipitation was observed up to step 8 of example 4.

Example 5 Preparation of 14-Hydroxymorphinone Sulfate

1. Oripavine (30.0 g, 101 mmol) was charged as a slurry in deionizedwater (45 mL) into a 300 mL jacketed vessel, overhead stirred andequipped with a temperature probe and an addition funnel.

2. The jacket temperature for the vessel was set to 22° C., and theslurry was stirred at 500 rpm.

3. Formic acid (30 mL, 700 mmol) was added into the vessel. The solidsreadily dissolved into solution upon addition of formic acid. During theformic acid addition, the temperature of the reaction mixture increasedto 30° C.

4. Sulfuric acid (2.5 mL, 45 mmol) was added to the solution, and thesolution was stirred at 500 rpm.

5. After the solution temperature had cooled below 25° C., hydrogenperoxide (10.25 mL, 119 mmol) was added to the reaction through theaddition funnel at a rate of 0.17 mL/minute.

6. After the hydrogen peroxide addition was complete, an additional 5 mLof deionized water was added to the reaction through the additionfunnel, and the reaction solution was allowed to stir (500 rpm) at 22°C., and the reaction progress was monitored by HPLC. After stirring for20 hours, approximately 15-20% of the oripavine was still present in thereaction mixture, based on HPLC area %.

7. The reaction mixture was heated to 30° C. and an additional 1.5 mL(17 mmol) of hydrogen peroxide was added to the reaction in one portion,to increase conversion of oripavine (greater than 99% conversion, asdetermined by HPLC).

8. The reaction mixture was stirred (500 rpm) at 30° C. for anadditional 16 hours.

9. Sulfuric acid (0.35 mL, 6.3 mmol) was added into the reaction, andthe solution was stirred (500 rpm) for 10 minutes.

10. Methanol (60 mL) was added into the reaction mixture, and the rateof stirring was reduced to 200 rpm.

11. The reaction mixture was cooled to 15° C. over 2.5 hours. Uponcooling, solids precipitated out of the solution forming a suspension.

12. The resulting suspension was stirred (200 rpm) at 15° C. for anadditional 1 hour.

13. The solids were filtered under vacuum using a Buchner funnel, withWhatman#1 filter paper, and the solids were collected and washed withmethanol (2×60 mL). A sample of the solids was analyzed by the HPLCmethod of Example 12, and was shown to contain 14-hydroxymorphinone with349 ppm of 8-hydroxyoxymorphone (based on HPLC area percent).

14. The solids were dried under vacuum on the Buchner funnel for 30minutes, before being transferred to a drying oven and dried undervacuum to a constant weight. The solids contained 18.09 g (26 mmol(calculated without water of crystallization), 51.5% yield) of14-hydroxymorphinone sulfate as fine yellow crystals, containing 349 ppmof 8-hydroxyoxymorphone (based on HPLC area percent in relation to14-hydroxymorphinone).

15. To see whether the yield can be increased, the filtrate and methanolwashes were returned to the jacketed vessel and tert-butyl methyl ether(60 mL) was added to the mixture. Upon addition of the tert-butyl methylether, solids precipitated out of the reaction mixture. The mixture wasstirred at 200 rpm and heated to 55° C.

16. After the solids had completely dissolved, the solution wasgradually cooled to 20° C. over 3 hours. The mixture was stirred (200rpm) at 20° C. for an additional 48 hours. Upon cooling and stirring,solids precipitated.

17. The solids were filtered under vacuum using a Buchner funnel, withWhatman#2 filter paper, washed with tert-butyl methyl ether (60 mL) anddried under vacuum on the Buchner funnel for 30 minutes, before beingtransferred to a drying oven and dried under vacuum to a constantweight. The solids contained 5.60 g (8 mmol (calculated without water ofcrystallization), 15.8% yield) of 14-hydroxymorphinone sulfate as tancrystals. The composition of the tan crystals was substantially the sameas the composition of the yellow crystals isolated initially, exceptthat it contained 2051 ppm, based on HPLC area percent, of8-hydroxyoxymorphone.

About 7.4 molar equivalents of total acid per molar equivalent oforipavine were used in this example. The molar ratio of sulfuric acid toformic acid was about 1:13.9. Precipitation was observed in step 11.

Example 6 Preparation of Oxymorphone Free Base

1. 14-Hydroxymorphinone sulfate (11.95 g, 17.2 mmol (calculated withoutwater of crystallization)) (i.e., solids from the first isolation ofExample 5 (yellow crystals)), deionized water (120 mL) and methanol (48mL) were charged into a 250 mL flask equipped with a magnetic stir bar.The majority of solids did not dissolve into solution at roomtemperature.

2. Formic acid (1.50 mL, 40 mmol) was added to the mixture, and themixture was stirred vigorously at 22° C. After 30 minutes of stirring at22° C., a large portion of the solid material remained insoluble.

3. The mixture was transferred from the flask to a high pressurereaction vessel equipped with a magnetic stir bar. Into the vessel wascharged 5% palladium on carbon (0.091 g) and the vessel was sealed.

4. The mixture was stirred at 750 rpm and heated to 40° C. The mixturewas hydrogenated at 60 psia (413.69 kPa) for 6 hours.

5. The reaction was vented, purged with nitrogen, vented andhydrogenated at 60 psia (413.69 kPa) for an additional 3 hours.

6. The reaction was vented, purged with nitrogen and cooled to 22° C.over 8 hours.

7. The reaction mixture was filtered through filter paper to remove thepalladium on carbon and the filtrate was sampled for HPLC analysis. Thesolution pH was 2.75. Analysis by the HPLC method of Example 12 showedthat the sample contained oxymorphone free base with 72 ppm of8-hydroxyoxymorphone (based on HPLC area percent in relation tooxymorphone free base) and 62 ppm of 14-hydroxymorphinone (based on HPLCarea percent).

8. While stirring at 200 rpm, the solution was basified by adding 7 mLof 28% ammonium hydroxide to the filtrate solution; solids precipitatedout of solution during the ammonium hydroxide addition and the final pHof the mixture was 9.06. Solids were isolated, dried at room temperatureunder vacuum and sampled by the HPLC method of Example 12. Analysis byHPLC showed that the solid sample contained oxymorphone free base with33 ppm of 8-hydroxyoxymorphone (based on HPLC area percent) and 17 ppmof 14-hydroxymorphinone (based on HPLC area percent).

9. The mixture was allowed to stir (200 rpm) at 22° C. for an additional30 minutes.

10. The solids were filtered under vacuum using a Buchner funnel, withWhatman#2 filter paper, washed with water (2×12 mL) and dried undervacuum on the Buchner funnel for 30 minutes, before being transferred toa drying oven and dried under vacuum to a constant weight at 80° C. for16 hours. The solids contained 7.89 g (26.2 mmol, 76% yield) ofoxymorphone (base) as a white crystalline powder, 52 ppm of8-hydroxyoxymorphone and 41 ppm of 14-hydroxymorphinone, based on theHPLC method of Example 12.

About 7.4 molar equivalents of total acid per molar equivalent oforipavine were used in example 5, i.e. during the oxidation. The molarratio of sulfuric acid to formic acid was about 1:13.9 during oxidation.

Example 7 Preparation of 14-Hydroxymorphinone Sulfate

14-Hydroxymorphinone sulfate was prepared as follows:

1. Into a 100 mL reaction vessel equipped with a temperature probe,overhead stirrer and reflux condenser, oripavine (3.02 g, 10.2 mmol) wascharged as a slurry in deionized water (9 mL).

2. The reaction mixture was stirred at 300 rpm, while maintaining aninternal temperature of 20° C.

3. Into the reaction was added 88% formic acid (6 mL, 139.9 mmol), andthe solids readily dissolved into solution. During the formic acidaddition, the temperature of the reaction mixture increased to 30° C.

4. After the solution temperature had cooled to 20° C., 35% hydrogenperoxide (1.06 mL, 15.8 mmol) and sulfuric acid (0.45 mL, 8.15 mmol)were added to the reaction.

5. The reaction was stirred (300 rpm) at 20° C. for 16 hours.

6. Stirring of the mixture was reduced to 75 rpm and the mixture wascooled to 0° C. over 1 hour. Solids began precipitating out of solutionafter the temperature of the mixture reached 15° C.

7. The mixture was stirred for an additional 1 hour at 0° C. The solidswere filtered under vacuum using a Buchner funnel with Whatman #1 filterpaper, and the filtered solids were washed with tert-butyl methyl ether(3×15 mL).

8. Additional solids precipitated out of the filtrate after thetert-butyl methyl ether washes were combined with the filtrate. Thesesolids were also filtered under vacuum using a Buchner funnel withWhatman #1 filter paper.

9. The two batches of solids were dried separately under vacuum on theBuchner funnel for 1 hour.

10. The solids were further dried in a vacuum oven at 80° C. for 16hours.

11. Isolated: 0.09 g of solid (14-hydroxymorphinone sulfate) from thefirst filtration with an HPLC peak area ratio of14-hydroxymorphinone:8-hydroxyoxymorphone equal to 6,340,697:312 (49.2ppm of 8-hydroxyoxymorphone), based on the HPLC method of Example 12.The auto-scaled chromatograph of the sample is depicted in FIG. 3.

12. Isolated: 2.33 g of solid from the second filtration with an HPLCpeak area ratio of 14-hydroxymorphinone:8-hydroxyoxymorphone equal to5,672,733:1,561 (275 ppm 8-hydroxyoxymorphone, based on HPLC areapercent), based on the HPLC method of Example 12. The auto-scaledchromatograph of the sample is depicted in FIG. 4.

About 14.5 molar equivalents of total acid per molar equivalent oforipavine were used in this example. The molar ratio of sulfuric acid toformic acid was about 1:17.1. Precipitation was observed in step 6.

Example 8 Preparation of 14-hydroxymorphinone sulfate

14-Hydroxymorphinone sulfate was prepared as follows:

1. Into a 100 mL jacketed vessel equipped with a temperature probe,overhead stirrer and an addition funnel, oripavine (20.0 g, 67.4 mmol)was charged as a slurry in deionized water (30 mL).

2. The jacket temperature for the vessel was set to 20° C. and theslurry was stirred at 300 rpm.

3. 88% formic acid (10 mL, 232 mmol) was added into the reactionmixture. The solids readily dissolved into solution upon this addition.During the formic acid addition, the temperature of the reaction mixtureincreased to 30° C.

4. Sulfuric acid (2.0 mL, 36 mmol) was added to the solution, and thesolution was stirred at 300 rpm.

5. After the solution temperature had cooled below 25° C., 35% hydrogenperoxide (7.00 mL, 81.4 mmol) was added to the reaction over 15 minutes,using the addition funnel.

6. After the peroxide addition was complete, an additional 3 mL ofdeionized water was added to the reaction through the addition funnel.

7. The reaction solution was allowed to stir (300 rpm) at 20° C. for 20minutes.

8. The reaction was then heated to 30° C. and held at 30° C., whilestirring at 300 rpm for 8 hours.

9. The reaction mixture was then cooled to 20° C. over 2 hours andstirred (300 rpm) for an additional 8 hours at this temperature. Solidsprecipitated out of solution during the cooling from 30° C. to 20° C.

10. The resulting suspension was treated with 20 mL of methanol and thesuspension was stirred at 20° C. for 30 minutes.

11. The solids were filtered under vacuum using a Buchner funnel withWhatman #1 filter paper, and the solids were washed with methanol (2×20mL).

12. The solids were dried under vacuum on the Buchner funnel for 1 hour,before being transferred to a drying oven and dried under vacuum at 80°C. for 16 hours.

13. 7.19 g of solid (26 mmol (calculated without water ofcrystallization) 14-hydroxymorphinone sulfate (73.2% yield)) wasisolated as fine yellow-white crystals and analyzed by the HPLC methodof Example 12. Analysis showed an HPLC area ratio of14-hydroxymorphinone:8-hydroxyoxymorphone of 8,873,042:623. In otherwords, the composition comprised 97.88% 14-hydroxymorphinone (based onHPLC area percent) and 70 ppm 8-hydroxyoxymorphone (based on HPLC areapercent). The auto-scaled chromatograph and peak results from thisanalysis are depicted in FIG. 5.

About 4.66 molar equivalents of total acid per molar equivalent oforipavine were used in this example. The molar ratio of sulfuric acid toformic acid was about 1:6.4. Precipitation was observed in step 9.

As compared to the previous example (Example 7), less total acid (formicacid plus sulfuric acid) was used (4.66 equivalents vs. 14.5equivalents), more sulfuric acid per formic acid was used (1:6.4 vs.1:17.1) and the conditions of the present reaction resulted in betteryield (73.2% vs. 67% 14-hydroxymorphinone sulfate).

Example 9 Preparation of 14-Hydroxymorphinone Sulfate

14-Hydroxymorphinone sulfate was prepared as follows.

1. Into an 80 mL reaction vessel equipped with a temperature probe andmagnetic stirrer, oripavine (10.0 g, 33.7 mmol) was dissolved indeionized water (20 mL) and 88% formic acid (3.60 mL, 84.0 mmol).

2. The solution was stirred (600 rpm) at 22° C. for 15 minutes.

3. Sulfuric acid (0.94 mL, 17 mmol) was added into the reaction mixture,and the solution was stirred at 600 rpm. After the solution temperaturehad cooled below 25° C., 35% hydrogen peroxide (3.20 mL, 37.2 mmol) wasadded to the reaction in one portion.

4. After the peroxide addition was complete, an additional 1 mL ofdeionized water was added to the reaction. The reaction solution wasallowed to stir (600 rpm) at 22° C. for 60 minutes.

5. The reaction was then heated to 30° C. over 20 minutes and held at30° C., while stirring at 600 rpm for 16 hours.

6. Solids started to precipitate out of solution while stirring at 30°C.

7. The reaction mixture was then cooled to 22° C.

8. The resulting suspension was treated with 20 mL of methanol and thesuspension was stirred at 22° C. for 5 minutes.

9. The solids were filtered under vacuum using a Buchner funnel withWhatman #1 filter paper, and the solids were washed with methanol (2×10mL).

10. The solids were dried under vacuum on the Buchner funnel for 30minutes, before being transferred to a drying oven and dried undervacuum at 80° C. for 16 hours.

11. 8.08 g (11.6 mmol (calculated without water of crystallization),68.8% yield) of 14-hydroxymorphinone sulfate was isolated as fineyellow-white crystals. Analysis by the HPLC method of Example 12 showedan HPLC area ratio of 14-hydroxymorphinone:8-hydroxyoxymorphone of8,743,438:885. In other words, the mixture contained 101 ppm8-hydroxyoxymorphone. The auto-scaled chromatograph and peak resultsfrom this analysis are depicted in FIG. 6.

About 3 molar equivalents of total acid per molar equivalent oforipavine were used in this example. The molar ratio of sulfuric acid toformic acid was about 1:5. Precipitation was observed in step 6.

The resulting 14-hydroxymorphinone sulfate was used as starting materialin the subsequent Example 10.

Example 10 Preparation of Oxymorphone from 14-Hydroxymorphinone Sulfate

1. Into a 300 mL hydrogenation vessel equipped with a magnetic stir bar,14-hydroxymorphinone sulfate obtained in Example 9 above (7.03 g, 10.1mmol (calculated without water of crystallization)), deionized water (70mL) and methanol (28 mL) were charged. The majority of solids dissolvedinto solution.

2. Formic acid (0.935 mL, 21.8 mmol) and 5% palladium on carbon (0.053g) were added into the reaction mixture.

3. The vessel was sealed, stirred at 750 rpm and heated to 40° C.

4. The mixture was then hydrogenated at 60 psia (413.69 kPa) for 5hours.

5. The reaction was vented, purged with nitrogen, vented andhydrogenated at 60 psia (413.69 kPa) for an additional 1 hour.

6. The reaction was vented, purged with nitrogen and cooled to 22° C.over 8 hours.

7. The reaction mixture was filtered through filter paper to remove thepalladium on carbon and the filtrate was sampled for the HPLC analysisof Example 12. The results showed that less than 1% 14-hydroxymorphinone(free base) remained (by HPLC area %).

8. The filtrate was transferred to a 250 mL Erlenmeyer flask equippedwith a magnetic stir bar and pH probe. The solution pH was 2.66.

9. While stirring at 200 rpm, the solution was basified by adding 5 mLof 28% ammonium hydroxide; solids precipitated out of solution duringthe ammonium hydroxide addition and the final pH of the mixture was9.13.

10. The mixture was allowed to stir (200 rpm) at 22° C. for anadditional 45 minutes.

11. The solids were filtered under vacuum using a Buchner funnel withWhatman#2 filter paper, and the solids were washed with water (2×10 mL).

12. The solids were dried under vacuum on the Buchner funnel for 2hours, before being transferred to a drying oven and dried under vacuumto a constant weight.

13. Isolated: 4.58 g (15.2 mmol, 75% yield) of oxymorphone (base) as awhite crystalline powder as analyzed by the HPLC method of Example 12.The HPLC area ratio ofoxymorphone:14-hydroxymorphinone:8-hydroxyoxymorphone was 39,612,808:231(6 ppm):9,518 (240 ppm). In other words, the composition contained98.54% oxymorphone base, 6 ppm 14-hydroxymorphinone, and 240 ppm8-hydroxyoxymorphone, based on HPLC area percent. The auto-scaledchromatograph and peak results from this analysis are depicted in FIG.7.

Over all, about 3.64 molar equivalents of total acid per molarequivalent of oripavine were used in Examples 9 and 10.

Example 11 Comparison of Different Amounts of Formic Acid for Making14-Hydroxymorphinone Sulfate

Five experiments were conducted in which oripavine was converted tooxymorphone free base, via an isolated 14-hydroxymorphinone saltintermediate. Reactions involved in this conversion are depicted inScheme 21:

In these 5 experiments, the formic acid content during the oxidationstep (first step in Scheme 21) was varied from 1.0 to 3.0 equivalentsper oripavine (1.0, 1.5, 2.0, 2.5, 3.0 equivalents). Sulfuric acid washeld constant at 0.51 equivalents. The experimental procedures ofExample 9 (oxidation conditions and isolation of the sulfate) andExample 10 (hydrogenation conditions, using 1.1 eq instead of 2.13 eqformic acid, see Scheme 21) were applied.

The resulting compositions were analyzed by the HPLC method of Example12. The results are shown in Table 1.

TABLE 1 Product (HPLC peak area ratio) Amount of formic acid 8-Hydroxy-14-Hydroxy- during oxidation oxymorphone morphinone Oxymorphone 1.0 eqHCO₂H 67 ppm 51 ppm 98.05% 1.5 eq HCO₂H 86 ppm 31 ppm 97.84% 2.0 eqHCO₂H 88 ppm 20 ppm 98.25% 2.5 eq HCO₂H 240 ppm   6 ppm 98.54% 3.0 eqHCO₂H 213 ppm  25 ppm 98.41%

The results show that isolation of 14-hydroxymorphinone sulfate mayoffer advantages in reducing the amounts of 8-hydroxyoxymorphone and14-hydroxymorphinone formed during conversion of oripavine tooxymorphone, improving volume efficiency of the oxidation step andpotentially reduce costs of manufacturing.

Example 12 HPLC Method

-   -   HPLC conditions were as follows:    -   Instrument: Waters 2695 HPLC system with Waters 966 Photodiode        Array Detector    -   Column: Waters XBridge C18 (150×3.0 mm; 3.5 μm)    -   Mobile phase:        -   Solution A: 10 mMol (pH-10.2) ammonium bicarbonate in water        -   Solution B: methanol    -   Flow rate: 0.30 ml/min    -   UV detection: 292 nm    -   Injection volume: 10 μl of a 1 mg/ml sample solution. Samples        were prepared by weighing 10±0.5 mg of sample and quantitatively        transferring it to a 10 mL volumetric flask. The solids were        dissolved in a 80:20 mixture of 0.085% phosphoric acid in water:        methanol.    -   Column temperature: 30° C.    -   Run Time: 42 minutes

Gradient Conditions (Linear Concentration Changes):

TABLE 2 Time Flow % A % B initial 0.30 90.0 10.0 1.00 0.30 90.0 10.05.00 0.30 78.0 22.0 16.00 0.30 60.0 40.0 22.00 0.30 53.0 47.0 26.00 0.3048.0 52.0 31.90 0.30 25.0 75.0 32.20 0.30 90.0 10.0 42.00 0.30 90.0 10.0

A representative HLPC chromatogram showing all relevant peaks isprovided in FIG. 8. The components corresponding to the peaks are givenin Table 3.

TABLE3 Components Peak Abbreviations Retention Time RRT14-Hydroxymorphinone FHM-N-Oxide 3.227 0.15 N-Oxide10-Hydroxyoxymorphone 10OH-OMN 10.767 0.50 8-Hydroxyoxymorphone 8OH-OMN14.641 0.68 14-Hydroxymorphinone FHM 17.544 0.82 HydromorphoneHydromorphone 19.120 0.89 Oxymorphone OMN 21.461 1.00 6β-Oxymorphol6bOH-OMN 22.485 1.04 6a-Oxymorphol 6aOH-OMN 23.451 1.09 Oripavine ORP23.794 1.11 8,14-Dihydrooripavine 8,14-DHO 26.385 1.23 Oxycodone OXY31.228 1.46The relative retention time (RRT) was calculated in relation tooxymorphone.

Example 13 Preparation of Oxymorphone Hydrochloride

A composition comprising 99.26% of oxymorphone hydrochloride, 95 ppm of14-hydroxymorphinone hydrochloride, and an amount of8-hydroxyoxymorphone hydrochloride below the limit of detection wasprepared as follows.

The reaction is shown in Scheme 22:

1. Into a 300 mL jacketed reaction vessel equipped with a temperatureprobe, reflux condenser, and overhead stirrer, oxymorphone (4.01 g, 12.5mmol), deionized water (6 mL) and isopropanol (IPA; 45 mL) were charged.The oxymorphone had a composition comprising 12 ppm of14-hydroxymorphinone, 98.36% of oxymorphone and 132 ppm of8-hydroxyoxymorphone, based on the HPLC method of Example 12.

2. The mixture was stirred at 250 rpm and the external jacket of thevessel was heated to 75° C.

3. When the internal temperature of the mixture had reached 40° C., 37%hydrochloric acid (1.08 mL, 13.2 mmol) was added to the reaction vessel.

4. When the internal temperature of the mixture had reached 68° C.,additional amounts of deionized water (2 mL) and isopropanol (5 mL) wereadded to the reaction vessel.

5. The external jacket of the vessel was heated to 80° C. When theinternal temperature of the mixture reached 72.3° C., all visible solidswere dissolved in the reaction mixture.

6. The mixture was stirred at 250 rpm for 30 minutes at a temperaturebetween 72-73° C., and then gradually cooled to 6° C., over 8 hours. Themixture was then stirred for an additional 8 hours at 6° C.

7. The resulting solids were filtered under vacuum using a Buchnerfunnel with Whatman#2 filter paper, and the solids were collected andwashed with a 20:1 mixture of isopropanol:deionized water (30 mL).

8. The solids were dried under vacuum on the Buchner funnel for 3 hours,before being transferred to a drying oven and dried under vacuum to aconstant weight. The solids contained 2.96 g (8.8 mmol, 69.9% yield) ofoxymorphone hydrochloride as fine white crystals, containing 95 ppm of14-hydroxymorphinone hydrochloride (based on HPLC area percent) and nodetectable amount of 8-hydroxyoxymorphone hydrochloride, based on theHPLC method of Example 12 (Table 4).

TABLE 4 Starting Oxymorphone HCl Material (dried solid) Filtrateoxymorphone 98.36% 99.26% 95.81% 14-hydroxymorphinone  12 ppm 95 ppm  73ppm 8-hydroxy-oxymorphone 132 ppm not detectable 368 ppm

The result shows that a starting composition comprising oxymorphone freebase, 8-hydroxyoxymorphone and 14-hydromorphinone, the8-hydroxyoxymorphone being present in an amount of 12 ppm and the14-hydroxymorphinone in an amount of 132 ppm can result, when subjectedto the treatment with hydrochloric acid as described in the presentexample, in a composition comprising oxymorphone hydrochloride and14-hydroxymorphinone or a salt thereof, the 14-hydroxymorphinone beingpresent in an amount of 95 ppm.

Example 14 Preparation of Oxymorphone Sulfate

1. Into a 300 mL hydrogenation vessel equipped with a magnetic stir bar,14-hydroxymorphinone sulfate (15.08 g, 21.64 mmol (calculated withoutwater of crystallization)), deionized water (150 mL) and 5% palladium oncarbon (0.121 g) were charged. The solids partially dissolved intosolution. The 14-hydroxymorphinone sulfate had a purity of 98.42% andcontained 786 ppm of 8-hydroxyoxymorphone, based on HPLC area percentusing the HPLC method of Example 12.

2. The vessel was sealed, stirred at 750 rpm and heated to 40° C.

3. The mixture was then hydrogenated at 60 psia (413.69 kPa) for 6hours.

4. The reaction was vented, purged with nitrogen and cooled to 22° C.over 8 hours.

5. The reaction mixture was filtered through filter paper to remove thepalladium on carbon. The filtered palladium on carbon was rinsed withdeionized water (50 mL) and the resulting rinsing solution was combinedwith the filtrate. The combined filtrate and rinsing solution wassampled for HPLC analysis by the HPLC method of Example 12. The resultsshowed that less than 10,000 ppm 14-hydroxymorphinone remained (based onHPLC area %).

6. The combined filtrate and rinsing solution was transferred to ajacketed vessel equipped with an overhead stirrer and temperature probe.

7. The solution was stirred at 100 rpm and cooled from ambienttemperature to 0° C. After the solution had cooled below 5° C., solidsprecipitated out of solution. The mixture was allowed to stir (100 rpm)at 0° C. overnight.

8. To the suspension was added tetrahydrofuran (45 mL) and solidsdissolved into solution.

9. The solution was treated with tert-butyl methyl ether (125 mL) andfurther cooled to −5° C. Solids precipitated out of solution below 0° C.The suspension was stirred at −5° C. for 2 hours.

10. The solids were filtered under vacuum using a Buchner funnel withWhatman#3 filter paper.

12. The solids were dried under vacuum on the Buchner funnel for 1 hour,before being transferred to a drying oven and dried under vacuum to aconstant weight.

13. Isolated: 6.98 g (9.96 mmol, 46% yield) of oxymorphone sulfate as awhite crystalline powder. HPLC analysis was performed using the HPLCmethod of Example 12. The HPLC area ratio ofoxymorphone:14-hydroxymorphinone:8-hydroxyoxymorphone was 5,348,916:566(106 ppm):316 (59 ppm). In other words, the composition contained 99.23%of oxymorphone, 106 ppm of 14-hydroxymorphinone, and 59 ppm of8-hydroxyoxymorphone, based on HPLC area percent.

Example 15 Preparation of 14-Hydroxymorphinone Sulfate

14-Hydroxymorphinone sulfate was prepared as follows:

1. In a 250 ml 3-necked flask equipped with a temperature probe andmagnetic stirring bar, oripavine (10.0 g; 33.6 mmol) was dissolved inde-ionized water (18 mL) and 98% formic acid (3.88 mL, 101 mmol). Thesolution warmed up to 25° C. The solution was stirred (500 rpm) at 21°C. for 5 minutes.

2. Concentrated sulfuric acid (96%, 1.01 mL, 18.2 mmol) was added. Thetemperature rose to 35° C. The mixture was stirred (500 rpm) at 21° C.for 20 min.

3. Hydrogen peroxide (35 wt % in H₂O, 3.61 mL, 42.16 mmol) was added andthe solution stirred (500 rpm) for 30 minutes at room temperature.

4. The mixture was then heated to 35° C. over 5 minutes and held at 35°C. and stirred (500 rpm) for 48 hours. Solids started to precipitateduring the stirring after 10 hours.

5. To the resulting suspension was added 2-butanol (36 mL) and thestirring continued for 30 min. The temperature decreased from 35° C. to26° C. during this time. The resulting slurry was cooled to 4° C. andrested at this temperature for 2 hours.

6. Filtration, washing with water:2-butanol (1:2, 12 mL) and thoroughdrying in vacuo afforded 14-hydroxymorphinone sulfate (10.5 g, 15.1 mmol(calculated without water of crystallization) 90% yield). No oripavineor 8-hydroxyoxymorphone was detectable by HPLC.

About 3.54 molar equivalents of total acid per molar equivalent oforipavine were used in this example. The molar ratio of sulfuric acid toformic acid was about 1:5.5. Precipitation was observed in step 4.

As compared to the previous examples (Examples 7 and 8), less total acid(formic acid plus sulfuric acid) was used (3.54 equivalents vs. 14.5equivalents and 4.66 equivalents), more sulfuric acid per formic acidwas used (1:5.5 vs. 1:17.1 and 1:6.4), and the conditions of the presentreaction resulted in better yield (90% vs. 67% and 73.2%14-hydroxymorphinone sulfate).

Example 16 Preparation of 14-Hydroxymorphinone Sulfate

14-Hydroxymorphinone sulfate was prepared as follows:

1. In a multi-neck flask equipped with a magnetic stir bar andtemperature probe, oripavine (9.96 g, 33.5 mmol) was dissolved inde-ionized water (18 mL) and 98% formic acid (3.88 mL, 101 mmol). Theresulting solution was stirred at ambient temperature.

2. Concentrated sulfuric acid (96%, 0.92 mL, 16.8 mmol) was added andthe mixture stirred at 450 rpm for 10 minutes. After addition of thesulfuric acid, the mixture heated to more than 30° C., then cooledagain.

3. When the temperature of the solution had dropped below 25° C.,hydrogen peroxide (35 wt % in H₂O, 3.8 mL, 44 mmol) was added and thesolution stirred at 450 rpm for 20 minutes at room temperature.

4. The mixture was then stirred at 35° C. internal temperature for 48hours.

5. To the warm mixture was added 2-butanol (36 mL) and the stirringcontinued for 30 min. The resulting slurry was cooled to 4° C. andrested at this temperature for 2 hours.

6. Filtration, washing with water:2-butanol (1:2, 12 mL) and thoroughdrying in vacuo afforded 14-hydroxymorphinone sulfate (9.94 g, 14.3 mmol(calculated without water of crystallization) 85.4% yield). No oripavineor 8-hydroxyoxymorphone was detectable by HPLC.

About 3.5 molar equivalents of total acid per molar equivalent oforipavine were used in this example. The molar ratio of sulfuric acid toformic acid was about 1:6.

In this example, 0.5 equivalents H₂SO₄ were used. As in Example 15(where 0.55 equivalents H₂SO₄ were used), compared to the previousexamples (Examples 7 and 8), less total acid (formic acid plus sulfuricacid) was used (3.5 equivalents vs. 14.5 equivalents and 4.66equivalents), more sulfuric acid per formic acid was used (1:6 vs.1:17.1 and 1:6.4), and the conditions of the present reaction resultedin better yield (85.4% vs. 67% and 73.2% 14-hydroxymorphinone sulfate).

Example 17 Preparation of 14-Hydroxymorphinone Sulfate

14-Hydroxymorphinone sulfate was prepared using two different amounts ofwater as follows:

1. In a multi-neck flask equipped with a magnetic stir bar andtemperature probe, oripavine (10.4 g, 35.0 mmol) was dissolved inde-ionized water (16 or 20 mL, respectively) and 98% formic acid (3.88mL, 101 mmol). The resulting solution was stirred at ambient temperature(500 rpm).

2. Concentrated sulfuric acid (96%, 1.02 mL, 18.5 mmol) was added andthe mixture stirred at 500 rpm for 20 minutes. After addition of thesulfuric acid, the mixture heated to more than 30° C., then cooledagain.

3. When the temperature of the solution had dropped below 25° C.,hydrogen peroxide (35 wt % in H₂O, 3.62 mL, 42 mmol) was added and thesolution stirred at 500 rpm for 30 minutes at room temperature.

4. The mixture was then stirred (750 rpm) at 35° C. internal temperaturefor 48 hours.

5. To the warm mixture was added 2-butanol (36 mL) and the stirringcontinued for 30 min. The resulting slurry was cooled to 4° C. andrested at this temperature for 2 hours.

6. Filtration, washing with water:2-butanol (1:2, 12 mL) and thoroughdrying in vacuo afforded 14-hydroxymorphinone sulfate (9.90 g, 14.21mmol (calculated without water of crystallization) 81.2% yield for 16 mlwater; 10.14 g, 14.56 mmol (calculated without water of crystallization)83.2% yield for 20 ml water). No oripavine or 8-hydroxyoxymorphone wasdetectable by HPLC.

This Example shows the same advantages as pointed out in Example 15.Moreover, it shows that in addition to the 1.8 ml water per g oripavineas used in Example 15, 1.5 and 1.9 ml water per g oripavine can alsoadvantageously be used.

Example 18 Preparation of 14-Hydroxymorphinone Sulfate

14-Hydroxymorphinone sulfate was prepared as follows:

1. In a multi-neck flask equipped with a magnetic stir bar andtemperature probe, oripavine (10.04 g, 33.8 mmol) was dissolved inde-ionized water (18 mL) and 98% formic acid (3.88 mL, 101 mmol). Theresulting solution was stirred (500 rpm) at ambient temperature.

2. Concentrated sulfuric acid (96%, 1.02 mL, 18.5 mmol) was added andthe mixture stirred for about 20 minutes. After addition of the sulfuricacid, the mixture heated to more than 30° C., then cooled again.

3. When the temperature of the solution had dropped below 25° C.,hydrogen peroxide (35 wt % in H₂O, 3.46 mL, 40.1 mmol, corresponding to1.2 eq.) was added and the solution stirred for 30 minutes at roomtemperature.

4. The mixture was then stirred at 35° C. internal temperature for 48hours.

5. To the warm mixture was added 2-butanol (36 mL) and the stirringcontinued for 30 min. The resulting slurry was cooled to 4° C. andrested at this temperature for 2 hours.

6. Filtration, washing with water: 2-butanol (1:2, 12 mL) and thoroughdrying in vacuo afforded 14-hydroxymorphinone sulfate (10.07 g, 14.5mmol (calculated without water of crystallization) 85.8% yield). Nooripavine or 8-hydroxyoxymorphone was detectable by HPLC.

As in Example 15 (where 1.25 equivalents of hydrogen peroxide wereused), compared to the previous examples (Examples 7 and 8), less totalacid (formic acid plus sulfuric acid) was used (3.55 equivalents vs.14.5 equivalents and 4.66 equivalents), more sulfuric acid per formicacid was used (1:5.5 vs. 1:17.1 and 1:6.4), and the conditions of thepresent reaction resulted in better yield (85.8% vs. 67% and 73.2%14-hydroxymorphinone sulfate).

In the preceding specification, the invention has been described withreference to specific exemplary embodiments and examples thereof. Itwill, however, be evident that various modifications and changes may bemade thereto without departing from the broader spirit and scope of theinvention as set forth in the claims that follow. The specification anddrawings are accordingly to be regarded in an illustrative manner ratherthan a restrictive sense.

1. A process for preparing a compound of formula V or a solvate thereof

from a compound of formula I or a salt or solvate thereof, the processcomprising:

(a) oxidizing the compound of formula I; and (b) adding an acid H⁺_(n)X^(n−) to the reaction mixture before, during and/or after theoxidation reaction, wherein, R¹ is —H, —(C₁-C₇)alkyl, aralkyl,—(C₂-C₆)alkenyl, —SiR³ ₃, —(C₃-C₇)cycloalkyl,—(C₁-C₇)alkyl-(C₃-C₇)cycloalkyl, —(C₃-C₇)cycloalkenyl,—(C₁-C₇)alkyl-(C₃-C₇)cycloalkenyl, —CR⁴ ₂—O—(C₁-C₆)alkyl, —C(halo)₃,—CH₂(halo), —CH(halo)₂, —SO₂R⁵, or an O-protecting group; R² is —H,—CH₃, —(C₂-C₇)alkyl, —(C₂-C₄)alkenyl, benzyl,—(C₁-C₇)alkyl-(C₃-C₇)cycloalkyl, —CN, or an N-protecting group; each R³is independently selected from aryl, —(C₁-C₆)alkyl and —(C₁-C₆)alkoxy;each R⁴ is independently selected from —H and —(C₁-C₆)alkyl; R⁵ is—(C₆-C₁₄)aryl or —(C₁-C₆)alkyl; X^(n−) is an anion selected from thegroup consisting of Cl⁻, HSO₄ ⁻, SO₄ ²⁻, methanesulfonate, tosylate,trifluoroacetate, H₂PO₄ ⁻, HPO₄ ²⁻, PO₄ ³⁻, oxalate, perchlorate, andany mixtures thereof; and n is 1, 2 or
 3. 2. (canceled)
 3. The processof claim 1, wherein R² is —CH₃ or —H.
 4. (canceled)
 5. The process ofclaim 1, wherein R¹ is —H.
 6. (canceled)
 7. The process of claim 1,wherein X^(n−) is SO₄ ²⁻ or trifluoroacetate. 8-10. (canceled)
 11. Theprocess of claim 1, wherein the compound of formula I is

and the compound of formula V is

or a solvate thereof. 12-17. (canceled)
 18. The process of claim 1,wherein the reaction mixture is maintained at a temperature of fromabout 30° C. to about 38° C. during the oxidation reaction.
 19. Theprocess of claim 1, comprising the additional step: (c) precipitatingthe compound of formula V or solvate thereof, wherein the precipitationis caused by the presence of the acid H⁺ _(n)X^(n−) in the reactionmixture. 20-27. (canceled)
 28. The process of claim 19, wherein theprecipitation is initiated and/or enhanced by adding an antisolvent.29-34. (canceled)
 35. The process of claim 1, wherein the oxidation instep (a) is performed in the presence of an oxidizing agent, wherein theoxidizing agent comprises or is at least one peracid. 36-37. (canceled)38. The process of claim 35, wherein the at least one peracid isgenerated in situ in the reaction mixture of step (a) from hydrogenperoxide and at least one acid.
 39. (canceled)
 40. The process of claim38, wherein the at least one peracid is selected from the groupconsisting of performic acid, peracetic acid, 3-chloroperoxybenzoicacid, potassium peroxymonosulfate, trifluoro peracetic acid, persulfuricacid, and any combinations of the foregoing.
 41. The process of claim40, wherein the at least one peracid is performic acid, which isgenerated in situ in step (a) from hydrogen peroxide and formic acid, orwherein the at least one peracid is a combination of performic acid andpersulfuric acid, which is generated in situ in step (a) from hydrogenperoxide, sulfuric acid and formic acid. 42-66. (canceled)
 67. Theprocess of claim 38, wherein the total amount of acid in the reactionmixture, including the acid H⁺ _(n)X^(n−) and the at least one acid usedfor generating the peracid, is from about 0.6 to about 14.0 molarequivalents of total acid per molar equivalent of the compound offormula I. 68-76. (canceled)
 77. The process of claim 35, wherein themolar amount of the acid used for generating the peracid is from about2.5 to about 4.5 molar equivalents per molar equivalent of the compoundof formula I, n is 2, and the molar amount of the acid H⁺ _(n)X^(n−) isfrom about 0.5 to about 0.6 molar equivalents per molar equivalent ofthe compound of formula I, and wherein the acid used for generating theperacid is formic acid, and the acid H⁺ _(n)X^(n−) is sulfuric acid. 78.(canceled)
 79. The process of a claim 1, wherein the compound of formulaV or the solvate thereof is precipitated and wherein the precipitationtemperature is in a range of from about 5° C. to about 22° C., and thetotal amount of acid present in the reaction mixture is from about 1 toabout 7 molar equivalents of total acid per molar equivalent of thecompound of formula I. 80-85. (canceled)
 86. The process of claim 1,wherein the compound of formula V is 14-hydroxymorphinone sulfate or ahydrate thereof. 87-105. (canceled)
 106. The process of claim 1, whereinthe compound of formula (I) is oripavine or a salt or solvate thereof,the oxidation agent comprises or is performic acid formed from hydrogenperoxide and formic acid, the acid H⁺ _(n)X^(n−) in step (b) is sulfuricacid which is added to the reaction mixture, and the compound of formulaV is 14-hydroxymorphinone sulfate or a solvate thereof. 107-112.(canceled)
 113. The process of claim 106, wherein the sulfuric acid instep (b) is added in an amount of from about 0.5 to about 0.55 molarequivalents per molar equivalent of the compound of formula I. 114-117.(canceled)
 118. The process of claim 106, which is performed by: (i)forming a solution or a suspension comprising the compound of formula I,from about 1.5 to about 2.0 ml water per g compound of formula I, andfrom about 2.5 to about 4.5 molar equivalents of formic acid per molarequivalent of compound of formula I, (ii) adding from about 0.5 to about0.6 molar equivalents of sulfuric acid per molar equivalent of thecompound of formula I to the solution or the suspension, (iii) addingfrom about 1.0 to about 1.4 molar equivalents of hydrogen peroxide tothe solution or the suspension from (ii), then incubating the mixture ata temperature of from about 30° C. to about 38° C. until the conversionis complete, and (iv) precipitating the compound of formula V from theresulting solution or suspension.
 119. The process of claim 224, whereinthe antisolvent is methanol, isopropanol, 2-butanol, tert-butyl methylether and/or tetrahydrofuran. 120-131. (canceled)
 132. The process ofclaim 1, with the proviso that the compound of formula V is not14-hydroxymorphinone triflate or 14-hydroxymorphinone chloride, or withthe proviso that the compound of formula V is not precipitated by addingthe reaction mixture after the oxidation reaction to a solventcontaining sulfuric acid, methanesulfonic acid, phosphoric acid or HCl,when R¹ is —H; and R² is selected from —H, —CH₃, optionally unsaturated—(C₂-C₆)alkyl, and —(C₁-C₄)alkyl substituted with a cycloalkyl group.133-134. (canceled)
 135. A compound having the formula V or a solvatethereof

wherein R¹, R², X^(n−) and n are defined as in claim
 1. 136-143.(canceled)
 144. The compound having the formula V of claim 135, which is

or a solvate thereof. 145-148. (canceled)
 149. The compound having theformula V of claim 135, with the proviso that the compound is not14-hydroxymorphinone triflate or 14-hydroxymorphinone chloride, or withthe proviso that when R¹ is —H; and R² is selected from —H, —CH₃,optionally unsaturated —(C₂-C₆)alkyl, and —(C₁-C₄)alkyl substituted witha cycloalkyl group, then the compound having the formula V is not

150-152. (canceled)
 153. A composition comprising the compound offormula V according to claim 135, which additionally comprises acompound of formula III

wherein R¹ and R² are defined as in the compound of formula V, or a saltor solvate thereof.
 154. (canceled)
 155. The composition of claim 153,wherein the amount of the compound of formula III in the composition isless than about 2500 ppm, less than about 2250 ppm, less than about 2000ppm, less than about 1750 ppm, less than about 1500 ppm, or less thanabout 1250 ppm of the compound of formula V (HPLC peak area ratio).156-171. (canceled)
 172. A process for preparing a compound of formulaIV or a salt or solvate thereof from a compound having formula V or asolvate thereof

the process comprising the steps of (e) providing a solution orsuspension of the compound having formula V or a solvate thereof; and(f) reducing the compound of formula V to the compound of formula IV,wherein R¹, R², X^(n−) and n are defined as in claim
 1. 173-177.(canceled)
 178. The process of claim 172, wherein the compound offormula IV is prepared in the form of its salt

wherein R¹, R², X^(n−) and n are defined as in claim 172, or a solvatethereof. 179-185. (canceled)
 186. The process of claim 172, additionallycomprising the step of preparing the salt or solvate of formula V byreacting a compound of formula (I) which is oripavine or a salt orsolvate thereof, with an oxidation agent which comprises or is performicacid formed in situ from hydrogen peroxide and formic acid, and addingan acid H⁺ _(n)X^(n−) which is sulfuric acid to the reaction mixture, toform a compound having formula V which is 14-hydroxymorphinone sulfateor a solvate thereat and obtaining a compound of formula IV which isoxymorphone or a salt or solvate thereof. 187-189. (canceled)
 190. Acompound of formula IV

wherein R¹ and R² are defined as in claim 172, or a pharmaceuticallyacceptable salt or solvate thereof, obtained by the process according toclaim
 172. 191. Oxymorphone trifluoroacetate or a pharmaceuticallyacceptable solvate thereof or oxymorphone sulfate or a pharmaceuticallyacceptable solvate thereof.
 192. (canceled)
 193. A compositioncomprising a compound of formula IV

wherein R¹ and R² are defined as in claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, which additionally comprises anamount of a compound of formula III

wherein R¹ and R² are defined as in claim 1, or a salt or solvatethereof, wherein the amount of the compound having the formula III inrelation to the amount of the compound having the formula IV is lessthan about 2500 ppm, less than about 2000 ppm, less than about 1500 ppm,less than about 1000 ppm, or less than about 500 ppm (HPLC peak arearatio). 194-195. (canceled)
 196. A composition comprising a compound offormula IV

wherein R¹ and R² are defined as in claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, which additionally comprises anamount of a compound of formula II

wherein R¹ and R² are defined as in claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, wherein the amount of the compoundof formula II in relation to the amount of the compound having theformula IV is less than about 500 ppm, less than about 250 ppm, lessthan about 200 ppm, less than about 100 ppm, less than about 50 ppm,less than about 40 ppm, or less than about 30 ppm (HPLC peak arearatio).
 197. (canceled)
 198. A composition comprising a compound offormula IV

wherein R¹ and R² are defined as in claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, which additionally comprises anamount of a compound of formula III

wherein R¹ and R² are defined as in 1, or a salt or solvate thereof, andwhich additionally comprises an amount of a compound of formula II

wherein R¹ and R², are defined as in 1, or a pharmaceutically acceptablesalt or solvate thereof, wherein the combined amount of the compound offormula II and III in the composition is less than about 3000 ppm, lessthan about 2500 ppm, less than about 2000 ppm, less than about 1500 ppm,less than about 1000 ppm, less than about 500 ppm, less than about 400ppm, or less than about 300 ppm in relation to the amount of thecompound of formula IV (HPLC peak area ratio). 199-202. (canceled) 203.The composition of claim 198, wherein the compound of formula IV isoxymorphone sulfate or a solvate thereof or oxymorphone trifluoroacetateor a solvate thereof. 204-216. (canceled)
 217. A method for treating orpreventing a medical condition selected from the group consisting ofpain, addiction, cough, constipation, diarrhea, insomnia associated withand/or caused by pain, cough or addiction, depression associated withand/or resulting from pain, cough or addiction, and combinations of twoor more of the foregoing in an animal, comprising administering to ananimal in need thereof an effective amount of the compound of formula IVor a pharmaceutically acceptable salt or solvate thereof according toclaim
 190. 218. A method for treating or preventing pain in an animal,comprising administering to an animal in need thereof an effectiveamount of the compound of formula IV or a pharmaceutically acceptablesalt or solvate thereof according to claim
 190. 219-232. (canceled) 233.A method for treating or preventing a medical condition selected fromthe group consisting of pain, addiction, cough, constipation, diarrhea,insomnia associated with and/or caused by pain, cough or addiction,depression associated with and/or resulting from pain, cough oraddiction, and combinations of two or more of the foregoing in ananimal, comprising administering to an animal in need thereof aneffective amount of the composition comprising a compound of formula IVor a pharmaceutically acceptable salt or solvate thereof according toclaim
 193. 234. A method for treating or preventing pain in an animal,comprising administering to an animal in need thereof an effectiveamount of the composition comprising a compound of formula IV or apharmaceutically acceptable salt or solvate thereof according to claim193. 235-242. (canceled)
 243. The process of claim 28, wherein theantisolvent is selected from the group consisting of tert-butyl methylether, diethyl ether, hexane(s), tert-amyl alcohol, methanol, ethanol,isopropanol, 2-butanol, heptanes, xylenes, toluene, acetone, 2-butanone,ethyl acetate, tetrahydrofuran, 1,2-dichloroethane, chloroform,dichloromethane, 1-methoxy-2-propanol, 2-ethoxyethanol, n-propanol,1-butanol, tert-butanol, isobutanol, isopropyl acetate, 1,4-dioxane,2-methyl-tetrahydrofuran, methyl formate, methyl acetate, and anymixtures of two or more of any of the foregoing.
 244. The process ofclaim 118, wherein step (iv) is performed by adding an antisolvent tothe solution.